Acute Inflammation Pathology PDF

21 PATHOGENESIS OF ACUTE INFLAMMATION ILOs By the end of this lecture, students will be able to 1. Evaluate process of Leukocyte recruitment to sites of inflammation under effect of certain cytokines. 2. Outline role of neutrophils and macrophages in clearance of the offending a...

21 PATHOGENESIS OF ACUTE INFLAMMATION ILOs By the end of this lecture, students will be able to 1. Evaluate process of Leukocyte recruitment to sites of inflammation under effect of certain cytokines. 2. Outline role of neutrophils and macrophages in clearance of the offending agent. 3. Classify types of acute Inflammation according to etiology, pathogenesis, and morphology. 4. Correlate subtypes of acute inflammation to corresponding clinical conditions. Leukocyte Recruitment to Sites of Inflammation: Neutrophils and macrophages are recruited to recognize invading pathogens and necrotic debris, eliminate them, and produce growth factors to facilitate repair. The type of leukocyte that emigrates into a site of injury depends on the original stimulus and the duration of the inflammatory response:  Bacterial infections tend to initially recruit neutrophils.  Viral infections recruit lymphocytes  Allergic reactions have increased eosinophils  Hypersensitivity reactions induce a mixed infiltrate.  Necrosis will initially induce a neutrophilic recruitment that predominate during the first 6 to 24 hours, then are replaced by monocytes after 24 to 48 hours. Leukocytes move from vessel lumen to tissue interstitium in a multistep process: 1. Margination, rolling, and adhesion of leukocytes to the endothelium 2. Transmigration across the endothelium 3. Migration in interstitial tissues toward a chemotactic stimulus (Chemotaxis) 4. After emigration, neutrophils are also short-lived; they undergo apoptosis after 24 to 48 hours, whereas monocytes survive longer. Leukocyte rolling and adhesion to endothelium  Occurs under the effect of progressive stasis of blood.  Rolling, adhesion, and transmigration occur by interactions between complementary adhesion molecules on leukocytes and endothelium.  The major adhesion molecule pairs are;  Selectins; mediate rolling and the initial weak interactions between leukocytes and endothelium.  Integrins; mediate the firm adhesion between leukocytes and endothelium.  Expression of these adhesion molecules is enhanced by secreted proteins called cytokines including (tumor necrosis factor (TNF), and interleukin (IL-1)). Leukocyte transmigration through endothelium Page 1 of 5   After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions.  Extravasation of leukocytes occurs mainly in postcapillary venules, the site at which there is maximal retraction of endothelial cells.  Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient.  After traversing the endothelium, leukocytes pierce the basement membrane by secreting collagenases, and they enter the extravascular tissue. Typically, the vessel wall is not injured during leukocyte transmigration. Chemotaxis of Leukocytes Chemotaxis is defined as locomotion along a chemical gradient. It means unidirectional movement of inflammatory cells towards site of injury.  After emigrating through interendothelial junctions and traversing the basement membrane, leukocytes move toward sites of injury along gradients of chemotactic agents (chemotaxis).  Mechanism; Chemotactic agents bind to specific leukocyte receptors; these trigger the polymerization of actin at the leading edge of the cell and facilitate cell movement in the direction of the locally produced chemoattractant. Leukocytes move by extending pseudopods that bind the extracellular matrix (ECM) and then pull the cell forward (front wheel drive).  Chemotactic agents include: 1. Exogenous bacterial products 2. Endogenous mediators, such as:  Complement fragments (particularly C5a)  Arachidonic acid (AA) metabolites (particularly LT B4)  Chemokines (e.g., interleukin-8). Phagocytosis and Clearance of the Offending Agent Phagocytosis involves three sequential steps: 1. Recognition and attachment of the particle to be ingested by the leukocyte by Phagocytic Receptors that recognizes microbes and not host cells. This is greatly enhanced when microbes are opsonized (coated) by specific proteins (opsonins) for which the phagocytes express high- affinity receptors. Examples of opsonins include IgG immunoglobulin and C3b. 2. Engulfment, with subsequent formation of a phagocytic vacuole (phagosome) that fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome 3. Killing or degradation of the ingested material: by reactive oxygen species (ROS), reactive nitrogen species, mainly derived from nitric oxide (NO), and lysosomal enzymes. Role of neutrophils and macrophages in clearance of the offending agent:  Neutrophils and monocytes contain granules packed with enzymes; lysozyme, myeloperoxidase, proteases and others, along with anti-microbial proteins that degrade microbes and dead tissues and may contribute to tissue damage. Page 2 of 5  ROS are produced within the phagolysosome. They include hydrogen peroxide which is converted to hypochlorite (by myeloperoxidase MPO in neutrophils) and hydroxyl radical; both of which are potent anti-microbial agents. Inducible nitric oxide synthase (iNOS) is expressed when macrophages are activated by cytokines (e.g., IFN-γ) or microbial products. iNOS induces the production of nitric oxide that reacts with superoxide to generate the highly reactive free radical peroxynitrite. Both nitrogen-derived free radicals and ROS attack and damage the lipids, proteins, and nucleic acids of microbes and host cells. Other functions of activated leukocytes: Activated leukocytes- especially macrophages also produce: Cytokines that can amplify or limit inflammatory reactions. Growth factors that stimulate endothelial cell and fibroblast proliferation and can drive collagen synthesis. Enzymes that remodel connective tissues.  NOTE:  In most forms of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours since they are more numerous in the blood than other leukocytes, respond more rapidly to chemokines, and attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as selectins.  After entering tissues, neutrophils are short-lived; they undergo apoptosis, disappear within 24 to 48 hours and are gradually replaced by monocyte-derived macrophages.  Macrophages not only survive longer but also may proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions.  Following recruitment of leukocytes, they are activated to undergo phagocytosis and intracellular killing. Termination of the Acute Inflammatory Response Inflammation declines in part because mediators are produced only transiently and typically have short half-lives. Inflammation is also regulated by stop signals that are activated. These include anti- inflammatory cytokines, such as transforming growth factor-β (TGF-β) and IL-10. The morphologic hallmarks of acute inflammatory reactions are: 1. Dilation of small blood vessels 2. Accumulation of leukocytes and fluid in the extravascular tissue. The vascular and cellular reactions account for the signs and symptoms of the inflammatory response:  Increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins (edema) and account for the redness (rubor), warmth (calor), and swelling (tumor) that accompany acute inflammation. Page 3 of 5   Leukocytes that are recruited and activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage and loss of function (functio laesa).  During the damage, and as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor). However, depending on the severity of the reaction, its specific cause, the particular tissue and site involved, special morphologic patterns often provide valuable clues to the underlying cause. Serous inflammation: Etiology and pathogenesis: Exudation of cell poor fluid into spaces created by injury to surface epithelia or into body cavities lined by the peritoneum, pleura, or pericardium. Typically, the fluid in serous inflammation is not infected by destructive organisms and does not contain large numbers of leukocytes. In body cavities the fluid may be derived from the plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation); accumulation of fluid in these cavities is called an effusion. Examples:  The skin blister resulting from a burn or viral infection  Peritoneal, pleural and pericardial serous effusions. Morphology: Accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin. Outcome: Resolution Fibrinous inflammation: Etiology and pathogenesis: A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus. With a large increase in vascular permeability, higher-molecular weight proteins such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. Examples: A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura. Morphology: Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Outcome: Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages. If the fibrin is not removed, with time, it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. Conversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac leads to opaque fibrous thickening of the pericardium and epicardium in the area of exudation and, if the fibrosis is extensive, obliteration of the pericardial space. Purulent (Suppurative) Inflammation and Abscess Page 4 of 5 Pathogenesis: Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. Etiology: The most frequent cause of purulent (also called suppurative) inflammation is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria. Example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of pus caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by seeding of pyogenic bacteria into a tissue. Morphology: Abscesses are composed of several layers; central region that appears as a mass of liquefied necrotic leukocytes and tissue cells. An intermediate zone of preserved neutrophils around this necrotic focus, and an outer region showing vascular dilation and parenchymal and fibroblastic proliferation, indicating chronic inflammation and repair. Outcome: In time the abscess may become walled off and ultimately replaced by connective tissue (healing by fibrosis). When persistent or at critical locations (such as the brain), abscesses may have to be drained surgically. Ulcers: An ulcer is a local defect of the surface epithelium of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue. Pathogenesis and aetiology: Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. Examples: (1) The mucosa of the mouth, stomach, intestines, or genitourinary tract. (2) The skin and subcutaneous tissue of the lower extremities in older persons who have circulatory disturbances that predispose to extensive ischemic necrosis. (3) Acute and chronic inflammation often coexist in ulcers, such as peptic ulcers of the stomach or duodenum and diabetic ulcers of the legs. Morphology:  Acute stage; there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect.  Chronic stage; the margins and base of the ulcer develop fibroblast proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 5 of 5  23 OUTCOMES OF ACUTE INFLAMMATION AND CHRONIC INFLAMMATION ILOs By the end of this lecture, students will be able to 1. Delineate outcomes of acute inflammation. 2. Evaluate factors that transform an acute inflammation into and chronic one.Relate specific and non-specific chronic inflammation to etiology, pathogenesis, chemical mediators and acting cells 3. Interpret non-specific chronic inflammation and granulomatous reaction in relation to corresponding clinical situations 4. Understand the underlying pathogenesis of the systemic effects of inflammation. Outcomes of Acute Inflammation Factors affecting the outcome of acute inflammation: 1. The nature of injury 2. The intensity of injury 3. The tissue involved 4. Host responsiveness Generally acute inflammation has one of three outcomes: Complete resolution: Resolution means restoration of the site of acute inflammation to normal. It involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics.  It is the usual outcome when: 1. The injury is limited or short-lived. E.g: Common cold. 2. There has been little tissue destruction. E.g: Small skin blisters. 3. The damaged parenchymal cells can regenerate. E.g: bone after a fracture or epithelium after a superficial skin wound). Such regeneration can occur through the proliferation of adjacent surviving cells or through the activity of tissue stem cells. Healing by connective tissue replacement (fibrosis): This occurs when: 1. There is substantial tissue destruction. Example: suppurative inflammation. Purulent pericarditis usually heals by fibrosis resulting in constrictive pericarditis or adhesive pericarditis. 2. The inflammatory injury involves tissues that are incapable of regeneration. Example: Burns involving a large area of the body. Page 1 of 5  3. There is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. The process of resolution of inflammatory exudates by fibrosis is called: organization. E.g: Some cases of fibrinous pericarditis in which excess fibrin is not removed. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue. Progression to chronic inflammation: Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either: 1. The persistence of the injurious agent. Example: Hepatitis C viral infection usually progresses to chronic inflammation due to persistence of viral particles in hepatocytes. 2. Some interference with the normal process of healing. Example: Diabetic ulcers. Chronic Inflammation Chronic inflammation is a prolonged process (weeks or months) in which active inflammation, tissue destruction, and healing all proceed simultaneously. It occurs in the following contexts: 1. After acute inflammation, as part of the normal healing process. 2. Due to persistence of an inciting stimulus or repeated bouts of acute inflammation. 3. As a low-grade( hidden reaction) without prior acute inflammation. Causes of Chronic Inflammation 1. Persistent infection by intracellular microbes (e.g., tubercle bacilli, viruses) of low direct toxicity but nevertheless capable of evoking immunologic responses 2. Hypersensitivity diseases, particularly reactions directed against self (e.g., autoimmune diseases) or abnormally regulated responses to normal host flora (inflammatory bowel disease) or benign environmental substances (allergy). 3. Prolonged exposure to potentially toxic exogenous (e.g., silica, causing pulmonary silicosis) or endogenous substances (e.g., lipids, causing atherosclerosis) 4. Diseases not conventionally considered inflammatory (e.g., neurodegenerative disorders [Alzheimer disease], metabolic syndrome, and cancers potentially driven by inflammation) Morphological features 1. Infiltration with mononuclear inflammatory cells, including macrophages, lymphocytes, and plasma cells 2. Tissue destruction, induced by persistent injury and/or inflammation 3. Attempts at healing by connective tissue replacement, accomplished by vascular proliferation (angiogenesis) and fibrosis Page 2 of 5 Types of chronic inflammation: 1. Chronic non-specific inflammation. 2. Granulomatous inflammation. Granulomatous Inflammation It is a distinctive form of chronic inflammation is characterized by focal accumulations of activated macrophages (granulomas); macrophage activation is reflected by enlargement and flattening of the cells (so-called epithelioid macrophages). Nodules of epithelioid macrophages in granulomatous inflammation are surrounded by a collar of lymphocytes elaborating factors necessary to induce macrophage activation. Activated macrophages may fuse to form multinucleated giant cells, and central necrosis may be present in some granulomas (particularly from infectious causes). Older granulomas can be surrounded by a rim of fibrosis. Causes of granulomatous inflammation: 1. Infectious etiologies: Tuberculosis, leprosy, syphilis, cat-scratch disease, schistosomiasis, certain fungal infections 2. Inflammatory causes: Temporal arteritis, Crohn disease, sarcoidosis 3. Inorganic particulates: Silicosis, berylliosis Types of granulomas include: 1. Foreign body granulomas are incited by particles that cannot be readily phagocytosed by a single macrophage but do not elicit a specific immune response (e.g., suture or talc). 2. Immune granulomas are formed by immune T cell-mediated responses to persistent, poorly degradable antigens. IFN-γ from activated T cells causes the macrophage transformation to epithelioid cells and the formation of multinucleated giant cells. The prototypical immune granuloma is caused by the tuberculosis bacillus; in that setting the granuloma is called a tubercle and classically exhibits central caseous necrosis. Page 3 of 5 Systemic Effects of Inflammation Systemic changes associated with inflammation are collectively called the acute phase response or—in severe cases—the systemic inflammatory response syndrome (SIRS). These represent responses to cytokines produced either by bacterial products (e.g., endotoxin) or by other inflammatory stimuli. The acute phase response consists of several clinical and pathologic changes: 1. Fever: Temperature elevation (1 to 4° C) occurs in response to pyrogens—substances that stimulate prostaglandin synthesis in the hypothalamus. For example, endotoxin stimulates leukocyte release of IL-1 and TNF that increase COX production of prostaglandins. In the hypothalamus, PGE2 resets the temperature set point. Aspirin reduces fever by inhibiting COX activity to block PG synthesis. 2. Acute-phase proteins: are plasma proteins mostly of hepatic origin; their synthesis increases several hundred-fold in response to inflammatory stimuli (e.g., cytokines, such as IL-6 and TNF). These include C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. CRP and SAA bind to microbial cell walls, acting as opsonins and fixing complement. They also help to clear necrotic cell nuclei and mobilize metabolic stores. Elevated fibrinogen leads to increased erythrocyte aggregation (increasing the erythrocyte sedimentation rate on ex vivo testing). Hepcidin is another acute-phase reactant responsible for regulating release of intracellular iron stores; chronically elevated hepcidin is responsible for the iron-deficiency anemia associated with chronic inflammation. 3. Leukocytosis (increased white cell number in peripheral blood) is common in inflammatory reactions; there is an accelerated release of bone marrow cells, typically with immature neutrophils in the blood (so-called shift to the left). Prolonged infection also induces proliferation of bone marrow precursors due to increased colony- stimulating factor (CSF) production. The leukocyte count usually climbs to 15,000 to 20,000 cells/μL.  Bacterial infections typically increase neutrophil numbers (neutrophilia)  Viral infections increase lymphocyte numbers (lymphocytosis)  Parasitic infestations and allergic disorders are associated with increased eosinophils (eosinophilia)  Certain infections (typhoid fever, rickettsiae, and some viruses and protozoans) are associated with decreased circulating white cell numbers due to increased consumption (leukopenia). 4. Other manifestations of the acute phase response due to cytokine effects on the central nervous system (CNS) include: o Increased pulse and blood pressure; Page 4 of 5  o Decreased sweating (due to blood flow diverted from cutaneous to deep vascular beds to limit heat loss) o Rigors (shivering) and chills o Anorexia, somnolence, and malaise. 5. In sepsis, organisms and/or endotoxin can stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1. High levels of these cytokines result in a clinical triad of disseminated intravascular coagulation (DIC), metabolic disturbances, and cardiovascular failure described as septic shock. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10 th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 5 of 5  22 Drugs Combating Acute Inflammation ILOs By the end of this lecture, students will be able to 1. Appraise the role of pharmacological inhibition of prostaglandins (PGs) actions in suppression of inflammation, pain, and fever. 2. Distinguish the benefits and hazards of inhibiting PGs on variable tissues. 3. Correlate the drugs differential inhibitory effects on COX enzymes to their clinical uses, adverse reactions, and contraindications. 4. Recommend a suitable drug in different relevant clinical scenarios. As previously discussed, prostaglandins (PGs) are considered the main mediators involved in inducing the manifestations of acute inflammatory response (Refer to mediators of acute inflammation). Therefore, drugs that can suppress the production of PGs are generally used in the management of acute inflammatory conditions. Suppression of PGs production can pharmacologically be achieved by two major classes of drugs, which differ in their chemical nature, and site and mechanism of action as shown in figure 1. 1. The steroidal anti-inflammatory, i.e., Corticosteroids, which are very effective anti-inflammatory drugs in addition to their immunosuppressant and anti-allergic properties. (Refer to drugs in allergy and anaphylaxis, Drugs modulating immune disorders). Corticosteroids suppress PGs production by preventing the release of their precursor, arachidonic acid, from the cell membrane phospholipid via inhibition of phospholipase A2 (PLA2). 2. The non-steroidal anti-inflammatory drugs (NSAIDs), which suppress PGs production by directly inhibiting their synthesis through the COX enzyme system, i.e., they are COX inhibitors. Fig. 1: Sites of action of drugs targeting the arachidonic acid pathway for anti-inflammatory and anti-allergic effects. Both classes of drugs are not specific to a particular disease and can be used in the vast majority of acute inflammatory disorders to relieve the manifestations of inflammation. It should be noted that Page 1 of 4 these drugs do not correct the underlying pathology and therefore, may be combined, when necessary, with other lines of treatment directed to the etiopathogenesis of the disease; for e.g., the use of antimicrobial drugs if inflammation is infectious in origin, etc. Another important principle is that though these drugs are first line in acute inflammation, there chronic use is not preferred, where they can be used only during periods of acute flare of chronic diseases to avoid the serious adverse effects of their long-term use. In the next section, the NSAIDs are discussed in more details, while the corticosteroids will be further studied in the Endocrine block. Non-steroidal anti-inflammatory drugs (NSAIDs) The key point to understand the actions of NSAIDs is to recognize and distinguish the consequences of inhibiting the COX enzyme non selectively (both COX-1 and COX-2) versus the selective inhibition of COX-2 alone, and also to relate these actions to the distribution of COX enzymes in the different tissues (Refer to mediators of acute inflammation). From the known functions of COX enzyme, it could be concluded that the therapeutic benefits of NSAIDs are related to inhibition of the excessive PGs produced by the induced COX-2 in response to the injurious agent. These PGs are mediators of inflammation and are responsible for the cardinal signs of the acute inflammatory response, including fever and pain. Therefore, the NSAIDs are used clinically for their: ▪ Anti-inflammatory effect in different types of inflammatory disorders as arthritis, myositis, etc. ▪ Analgesic effect for mild to moderate painful conditions as headache, toothache, rheumatic pain, dysmenorrhea, etc. ▪ Antipyretic effect to reduce body temperature in case of fever. Accordingly, NSAIDs are commonly referred to as analgesic antipyretic drugs or sometimes as non- opioid analgesics, to differentiate them form the opioid analgesics, which are used in severe types of pain and have potential for drug dependence. On the other hand, most of the adverse reactions of NSAIDs would be generally related to inhibition of the physiologically important prostanoids (PGs, prostacyclin, and thromboxane), which are the products of the constitutively active COX-1 enzyme (and in some instances COX-2) under normal conditions and play important roles in various tissues, including gastric protection, regulation of platelet activity, and renal functions. In this respect, it may be predicted that the selective COX-2 inhibitors are better drugs with less adverse effects. However, it was proven, after their wide clinical use, that they have more cardiovascular hazards than the non-selective agents because of their unopposed activating effect on platelet aggregation, as will be discussed below. Therefore, broadly the NSAIDs can be classified into: I. Non-selective COX inhibitors, which can further be categorized into A. Reversible non-selective COX inhibitors (Conventional non-salicylates NSAIDs), e.g., Ibuprofen, diclofenac, etc. These drugs differ from each other in their chemical nature, Page 2 of 4  pharmacokinetics, and their affinity to COX-1 and COX-2. Therefore, they have variable analgesic, anti-inflammatory activities, as well as variable severity of their adverse reactions. For example, Ketorolac is the most effective analgesic up to the analgesic effect of opioids and can be used to relief moderately severe pain as post-operative pain, but it is the most gastric injurious agent. Ibuprofen is less effective but a more tolerable NSAID. B. Irreversible non-selective COX inhibitor (Aspirin = Acetyl salicylic acid): Though it is the prototype NSAID, its use is replaced for most of the clinical indications by the other non- salicylates NSAIDs and is now mostly limited for its antiplatelet action by using a low dose. The low dose aspirin inhibits only thromboxane (TXA2) synthesis in the platelet, while it does not affect that of prostacyclin (PGI2) by the endothelial cells, favoring an antiaggregatory effect. The irreversible COX inhibition by aspirin ensures a maintained antiplatelet action for the lifetime of the platelet as being non-nucleated it can’t synthesize COX-1 again. On the other hand, if any minor inhibition of endothelial prostacyclin occurs, the endothelial cells are capable of synthesizing new enzyme. Therefore, the main use of aspirin now is the primary or secondary prophylaxis against thrombotic event in patients at risk as those with ischemic cardiovascular or cerebrovascular diseases. At moderate doses, aspirin exerts an analgesic effect, while at high doses, it shows its anti- inflammatory activity, which justifies its use in some cases of rheumatic fever to prevent complications. Adverse reactions: As explained above, the adverse effects of NSAIDs are due to their inhibitory effect on the constitutively produced COX enzyme system that plays a role in normal physiological functions resulting in: 1. The stomach: leading to gastric irritation, ulceration, and bleeding. Moreover, the acidic nature of some NSAIDs, like aspirin, minorly contributes to the gastric irritation, therefore they are better given with meals. Concomitant administration of proton pump inhibitors (drugs which inhibit gastric acid formation) can be used to provide prophylaxis against NSAIDs-induced injury in patients at risk of peptic ulcer. 2. The kidney: leading to analgesic nephropathy especially with prolonged use. 3. Hypersensitivity reactions: Blocking of the COX inflammatory pathway leads to diversion of the arachidonic acid pathway to the LOX pathway with further production of leukotrienes that may precipitate allergic reactions in the form of bronchospasm, urticaria, or angioedema in predisposed individuals. 4. The platelets: leading to increased risk of bleeding or thrombosis according to the drug used. Many of the members of this class are available as topical formulations to provide some benefit, while avoiding the systemic adverse effects. II. Selective COX inhibitors (Coxibs) e.g., celecoxib This drug subclass has the same properties as the conventional NSAIDs, but are characterized by: ▪ Less or minimal gastric injury. Page 3 of 4  ▪ No antiplatelet action, conversely, they can increase thrombotic risk by inhibiting the endothelial PGI2 in favor of the effect of platelet TXA2. Therefore, they are contraindicated in patients at cardiovascular risk of thrombosis, e.g., diabetic hypertensive patients. Paracetamol (Acetaminophen) Paracetamol is an analgesic antipyretic drug that lacks the anti-inflammatory activity that is why, it does not belong to the NSAID group. The key point to understand the difference between paracetamol and NSAIDs is that it mainly inhibits the COX enzyme centrally (in the CNS) and does not affect the peripheral COX present elsewhere in the body. This, in turn, accounts for the following properties: ▪ Weak or no anti-inflammatory activity ▪ No effect on platelet aggregation ▪ No gastric or renal injury Therefore, paracetamol is preferably used for fever or pain in absence of inflammation or in combination with NSAIDs in inflammatory disorders to decrease their doses and hence their adverse effects. It is also a safe analgesic antipyretic for children and during pregnancy. N.B., Acute overdose of paracetamol carries the risk of hepatic toxicity (Acute necrotizing hepatitis that could be fatal). Therefore, the maximum allowed dose of paracetamol is 3-4 g daily in healthy adults. Page 4 of 4  25 FACTORS MODULATING REPAIR ILOs By the end of this lecture, students will be able to 1. Apply steps of repair to healing in simple and complicated surgical wounds and parenchymal organs. 2. Delineate factors that influence tissue repair and abnormalities in tissue repair Factors That Influence Tissue Repair 1. Nutritional status of the host. 2. Metabolic status (diabetes mellitus delays healing). 3. Circulatory status or vascular adequacy. 4. Hormones (e.g., glucocorticoids can impede the inflammatory and reparative process). 5. Size and location: Well-vascularized tissues heal faster; inflammation in tissue spaces (e.g., peritoneal cavity) develops exudates that can either resolve or undergo organization. 6. Type of tissue: Labile and stable tissues have better tissue regeneration, whereas permanent tissues form only scar. 7. Local factors that delay healing include infections, ischemia, mechanical forces (e.g., motion or wound tension), and foreign bodies. Selected Clinical Examples of Tissue Repair and Fibrosis Healing of Skin Wounds A. Healing by First Intention (or Primary Union): Healing by first intention (or primary union) occurs when injury involves only the epithelial layer. Repair is mainly by epithelial regeneration. In a clean, uninfected surgical incision approximated by surgical sutures there is only focal disruption of the basement membrane and relatively minimal cell death. Steps of wound healing by first intention: 1. Wounding activates coagulation pathways; the clot (containing fibrin, fibronectin, and complement proteins) stops the bleeding and acts as a scaffold for migrating cells. As dehydration occurs, a scab is formed. 2. Within 24 hours, neutrophils arrive at the incision margin, releasing proteolytic enzymes that begin to clear the debris. 3. Within 24 to 48 hours, epithelial cells from both edges have migrated and proliferated along the dermis, depositing basement membrane components as they progress. Page 1 of 4  4. By day 3, neutrophils have been largely replaced by macrophages, and granulation tissue progressively invades the incision space, with collagen fibers evident at the incision margins. 5. By day 5, neovascularization reaches its peak with ongoing migration of fibroblasts, which are producing ECM proteins. The epidermis recovers its normal thickness as differentiation of surface cells yields a mature epidermal architecture with surface keratinization. 6. During the second week, there is continued collagen accumulation and fibroblast proliferation, but leukocyte infiltrate, edema, and vascularity are diminished. 7. By 4 weeks, scar is well formed with few inflammatory cells. Although the epidermis is essentially normal, dermal appendages destroyed in the line of the incision are permanently lost. B. Healing by Second Intention (or Secondary Union): Healing by second intention (or secondary union) happens when tissue loss is more extensive (e.g., large wounds, abscesses, ulceration, and ischemic necrosis [infarction]). repair involves a combination of regeneration and scarring. The inflammatory reaction is more intense, and there is abundant granulation tissue, with subsequent increased ECM accumulation and formation of a large scar, followed by myofibroblast wound contraction. Steps of wound healing by second intention: 1. In wounds causing large tissue deficits, inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed. 2. Much larger amounts of granulation tissue are formed. 3. The original granulation tissue scaffold is eventually converted into a pale, avascular scar; although the epidermis recovers its normal thickness and architecture, dermal appendages are permanently lost. 4. Wound contraction generally occurs in large surface wounds; within 6 weeks, large skin defects can be contracted to 5% to 10% of their original size. Wound Strength After suture removal at 1 week, wound strength is approximately 10% of that of unwounded skin. Tensile strength progressively increases through collagen synthesis during the first 2 months of healing, and at later times from structural modifications of collagen fibers (cross-linking, increased fiber size). Wound strength reaches approximately 70% to 80% of normal by 3 months but usually does not substantially improve beyond that point. Page 2 of 4 Fibrosis in Parenchymal Organs Fibrosis in parenchymal organs denotes abnormal deposition of collagen in the setting of chronic (often inflammatory) diseases. The basic mechanisms of fibrosis are the same as those of scar formation (largely driven by TGF-β). Fibrosis can cause substantial organ dysfunction and even organ failure (e.g., liver cirrhosis, fibrosing diseases of the lung [idiopathic pulmonary fibrosis, and drug- or radiation-induced pulmonary fibrosis], end-stage kidney disease, and constrictive pericarditis). Abnormalities in Tissue Repair Deficient scar formation: Inadequate granulation tissue or collagen deposition and remodeling can lead to either wound dehiscence or ulceration. This occurs most frequently after abdominal surgery and is a result of increased abdominal pressure, such as may occur with vomiting, coughing, or ileus. Excessive repair:  Exuberant granulation tissue (proud flesh): characterized by the formation of excessive amounts of granulation tissue, which protrudes above the level of the surrounding skin and blocks reepithelialization. Excessive granulation must be removed by cautery or surgical excision to permit restoration of epithelial continuity.  Hypertrophic scar: Excessive collagen accumulation forms a raised hypertrophic scar. These often grow rapidly and contain abundant myofibroblasts, but they tend to regress over several months. Hypertrophic scars generally develop after thermal or traumatic injury that involves the deep layers of the dermis.  Keloid: Progression beyond the original area of injury without subsequent regression is termed a keloid. Certain individuals seem to be predisposed to keloid formation, particularly those of African descent.  Desmoids (aggressive fibromatosis): incisional scars or traumatic injuries may be followed by exuberant proliferation of fibroblasts and other connective tissue elements that may recur after excision. Formation of contractures: Although wound contraction is a normal part of healing, an exaggerated process is designated a contracture. It will cause wound deformity (e.g., producing hand claw deformities or limit joint mobility). Contractures are commonly seen after serious burns and can compromise the movement of joints. Defects in Healing: Chronic Wounds: 1. Venous leg ulcers: develop most often in elderly people as a result of chronic venous hypertension, which may be caused by severe varicose veins or Page 3 of 4  congestive heart failure. These ulcers fail to heal because of poor delivery of oxygen to the site of the ulcer. 2. Arterial ulcers: develop in individuals with atherosclerosis of peripheral arteries, especially associated with diabetes. The ischemia results in atrophy and then necrosis of the skin and underlying tissues. 3. Pressure sores: are areas of skin ulceration and necrosis of underlying tissues caused by prolonged compression of tissues against a bone, for example, in bedridden, immobile elderly individuals with numerous morbidities. The lesions are caused by mechanical pressure and local ischemia. 4. Diabetic ulcers: affect the lower extremities, particularly the feet. Tissue necrosis and failure to heal are the result of small vessel disease causing ischemia, neuropathy, systemic metabolic abnormalities, and secondary infections. Histologically, these lesions are characterized by epithelial ulceration and extensive granulation tissue in the underlying dermis References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 4 of 4  27 Molecular Basis of Cancer: Genetic Alterations ILOs By the end of this lecture, students will be able to 1. Discuss general basic concept of cancer development. 2. Outline the Hallmarks of cancer. 3. Explore mechanisms of oncogene activation and tumor suppressor gene inactivation. 4. Apply the two-hit theory in the process of carcinogenesis. Molecular basis of cancer The mechanism as to how a normal cell is transformed to a cancer cell is complex. At different times, attempts have been made to unravel this mystery by various mechanisms. General basic concept of cancer; Monoclonality of tumors; Tumors are monoclonal in origin, they originate from a single progenitor cell line, opposite to the polyclonal population of non-neoplastic tissues. Multi-step process of cancer growth , Molecular studies have revealed that Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks. The various causes may act on the cell one after another (multi-hit process). Tumor heterogeneity, as a result of continuing mutation, tumor cells are genetically heterogeneous by the time of their clinical presentation, and behavior. Tumor progression continuous mutations is also involved in further progression of the genetically and phenotypically transformed malignant cells acquiring greater malignant potential and more aggressive behaviour with excessive growth, survival, invasiveness, distant metastasis and immune evasion. Genetic theory of cancer , In cancer, there are either genetic abnormalities in the cell, or there are normal genes with abnormal expression. The genetic abnormalities may be from inherited or induced mutations (induced by etiologic carcinogenic agents namely: chemicals, viruses, radiation). Eventually, the mutated cells transmit their characters to the next progeny of cells and result in cancer. Genetic regulators of cell cycle, and Cancer genes Cell cycle and division is controlled by regulatory genes that control mitosis, cell ageing, and termination in cell death by apoptosis. In normal cell growth, there are 4 regulatory genes that whenever damaged or abnormal, they can contribute directly to the malignant behaviour of cells. i) Proto-oncogenes; Growth-promoting genes that encode for cell proliferation pathway, make cell growth possible, inhibiting cell differentiation. These processes are all essential for cells to maintain healthy tissues and organs in the body. These could be a growth factor bound to cell surface receptors, signal-transduction proteins, or transcription factors. Page 1 of 4  Oncogenes: Oncogenes are mutated or overexpressed versions of normal cellular proto-oncogenes. Activation of growth-promoting oncogenes promotes increased cell growth and proliferation. They are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect. Examples of oncogenes; The Ras gene; that encode an intracellular signal-transduction protein (one of the on-and-off switches in cell growth pathway. When Ras mutates, it encodes for a protein that causes an uncontrolled growth-promoting signal. Ras gene mutations is associated with cancer of urinary bladder, pancreas, lung, colon and thyroid. The HER2 gene makes protein receptors that are involved in the growth and division of cells in the breast cancer. The Myc gene is associated with lymphoma. ii) Growth suppressor genes \ antioncogenes [Gate keeper of the genome]: Tumor suppressor genes are responsible for; control the progression of a specific stage of the cell cycle, inhibit the replication of the cell, stop the cell cycle in response to DNA damage, signal for the self-destruction of the cell and repair mistakes in DNA. Tumor suppressor genes; Inactivation, mutation or loss of growth-suppressor genes allow the transformed phenotype to proliferate. They are considered recessive genes; often both normal alleles must be damaged for transformation to occur. Examples; P53 gene, Guardian of the genome, normally prevents genome mutations. it is the most commonly mutated gene in cancer cells, found in more than half of cancers. Mutated in Bladder cancer, breast cancer, brain cancers. Retinoblastoma (RB) genes, mutated in the majority of cancers, particularly retinoblastoma of the eye in children and osteosarcoma. iii) Apoptosis regulatory genes control the programmed cell death. Mutation in apoptosis genes inhibit apoptosis and allow survival of abnormal cells with DNA defects and tumor progression [rather than stimulating proliferation]. Examples; BCL2 is an anti-apoptotic gene overexpressed, in follicular lymphoma. iv) DNA repair genes are those normal genes which regulate the repair of DNA damage that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes. Failure of DNA repair genes (Caretakers): maintain the integrity of the DNA during replication and correct DNA damage that occurs as a result of exposure to environmental factors. The loss of function in a recessive way results in accumulation of mutations in Tumor Suppressor Genes and oncogenes. Hallmarks of Cancer It appears that all cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer: Page 2 of 4  1. Self-sufficiency in growth signals; Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation. 2. Insensitivity to growth-inhibitory signals, Tumors may not respond to molecules that inhibit the proliferation of normal cells, usually because of inactivation of tumor suppressor genes that encode components of growth inhibitory pathways. 3. Evasion of apoptosis, Tumors are resistant to programmed cell death. 4. Limitless replicative potential (immortality), Tumors have unrestricted proliferative capacity, a stem cell–like property that permits tumor cells to avoid cellular senescence and mitotic catastrophe. 5. Sustained angiogenesis, Tumor cells, like normal cells, are not able to grow without a vascular supply to bring nutrients and oxygen and remove waste products. Hence, tumors must induce angiogenesis. 6. Ability to invade and metastasize. Tumor metastases are the cause of the vast majority of cancer deaths and arise from the interplay of processes that are intrinsic to tumor cells and signals that are initiated by the tissue environment. 7. Ability to evade the host immune response. Cancer cells exhibit a number of alterations that allow them to evade the host immune response. 8. Altered cellular metabolism. Tumor cells undergo a metabolic switch to aerobic glycolysis, which enables the synthesis of the macromolecules and organelles that are needed for rapid cell growth. Genetic aberrations causing oncogene activation and tumor suppressor gene inactivation: Mutation of normal genes may occur by four main mechanisms: 1. Point mutations: An alteration of a single base in the DNA chain. Can either activate or inactivate the protein products of the affected genes depending on their precise position and consequence. Point mutations that convert proto-oncogenes into oncogenes generally produce a gain-of-function, as in RAS gene mutation. By contrast, point mutations in tumor suppressor genes reduce or disable the function of the encoded protein, P53 gene mutation. 2. Gene rearrangements: Gene rearrangements may be produced by chromosomal translocations or inversions. A. Philadelphia (Ph) chromosome, in chronic myeloid leukemia A piece of chromosome 9 with ABL gene and a piece of chromosome 22 with BCR gene break off and trade places [ balanced reciprocal translocation], encoding a novel tyrosine kinase with potent transforming activity. BCR-ABL fusion gene. B. MYC In Burkitt lymphoma; the cells have a translocation between chromosomes 8 and 14 that leads to overexpression of the proto-oncogenes MYC gene on chromosome 8 by removing it from their normal regulatory elements and juxtaposition with inappropriate regulatory gene on chromosome 14 placing it under control of an, highly active promoter or enhancer. 3. Deletions: Deletion of specific regions of chromosomes may result in the loss of particular tumor suppressor genes. Page 3 of 4  Example: deletion of 17p is associated with loss of TP53, arguably the most important tumor suppressor gene. 4. Gene amplifications: Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins. Example: HER2 gene in breast cancers. Clinical Value of determining cancer genes; Targeted gene therapies target oncogenes and not tumor suppressor genes. They use drugs to target cancer cells while leaving healthy cells mostly undamaged. Targeted gene therapy modifies specific genes in cancer cells. Genetic testing is a tool that can be used to learn about inherited cancer risks. Some examples of cancers where specific genes appear to play a role in cancer risk include: breast, colon, prostate and ovary. Page 4 of 4  L26 CHARACTERS OF BENIGN VERSUS MALIGNANT TUMORS ILOs By the end of this lecture, students will be able to 1. Relate nomenclature of tumors to their tissue of origin. 2. Explain the relation between Metaplasia, Dysplasia, and Carcinoma in Situ to malignancy. 3. Differentiate between benign and malignant tumors as regards rate of growth, anaplasia, differentiation, invasion and metastasis. Nomenclature The terms neoplasm, “new growth” or “tumor” refer to abnormal masses of tissue. Definition; In contrast to non-neoplastic proliferations, Tumor is a new growth, that is autonomous, exceeds growth of normal tissues and persists after cessation of the initiating stimulus. A more modern definition; Neoplasm is a genetic disorder of cell growth that is triggered by acquired or ‘less commonly’ inherited mutations affecting a single cell and its clonal progeny. All tumors have two basic components: 1- Tumor parenchyma composed of clonal expansions of neoplastic cells. The classification of tumors and their biologic behavior are based primarily on the parenchymal component. 2- Supporting stroma composed of non-neoplastic connective tissue and blood vessels; abundant collagenous stroma is called desmoplasia. Tumor growth and spread are critically dependent on their stroma. Tumors are broadly classified based on clinical behaviors: Benign—with an “innocent” behavior characterized by a localized lesion without spread to other sites and amenable to surgical resection; the patient typically survives—although there are exceptions. Malignant—called cancers, with aggressive behavior including invasion and destruction of adjacent tissues, and capacity for spread to other sites (metastasis). Benign tumors typically end with the suffix -oma; o Benign mesenchymal tumors include lipoma, fibroma, angioma, osteoma, and leiomyoma. o Benign epithelial tumors also typically use the -oma suffix but in addition incorporates elements of histogenesis, macroscopic appearance, and microscopic architecture:  Adenomas: Epithelial tumors arising in glands or forming glandular patterns. Examples; adenoma of solid organs as kidney and liver, and endocrine organ adenoma, as thyroid, pituitary gland, ect… Page 1 of 4   Cystadenomas: Adenomas producing large cystic masses, common in ovary.  Papillomas: Surface Epithelial tumors forming gross or microscopic finger like projections, as skin papilloma and breast duct papilloma.  Polyp: A neoplasm-benign or malignant-produces a grossly visible projection above a mucosal surface, for example, into the gastric or colonic lumen. If the polyp has glandular tissue, it is called an adenomatous polyp (e.g., a colon polyp) It is worth emphasizing that some tumors do not follow the -oma rule; for example, melanoma, lymphoma, and mesothelioma are all malignant. Malignant tumors are categorized as the following:  Carcinomas derived from epithelium cells whether ectodermal or endodermal in origin. Sarcomas of mesenchymal cell origin. Mesenchymal tumors of blood-forming cells are called leukemias, and tumors of lymphocytes or their precursors are called lymphomas. The nomenclature for specific malignant tumors is based on their appearance and/or presumed cell of origin. Malignant epithelial tumors; Squamous Cell Carcinoma originates from Stratified squamous epithelial. Commonly found on the skin, mouth, esophagus, or vagina. Transitional cell carcinoma originates from transitional epithelium of urinary bladder. Adenocarcinomas, tumors with glandular epithelial origin. Malignant mesenchymal tumors; Sarcomas are designated by the appropriate cell prefix (e.g., smooth muscle malignancies are leiomyosarcomas). Neoplasms composed of poorly differentiated unrecognizable cells can only be designated as undifferentiated malignant tumors. Special tumor forms: Some tumors appear to have more than one parenchymal cell type: Mixed tumors derive from a neoplastic clone of a single germ cell layer that differentiates into more than one cell type (e.g., pleomorphic adenoma \ mixed salivary gland tumors containing epithelial cells mixed with myxoid and chondroid stroma). Teratomas; tumors that arise from totipotential cells capable of forming endodermal, ectodermal, and mesenchymal tissues. They are composed of various parenchymal cell types representative of more than one germ cell layer, and can have both benign and malignant forms. Such tumors typically occur in testis or ovary or rarely midline embryonic rests. Characteristics of Benign and Malignant Neoplasms Classification of a tumor as benign or malignant ultimately depends on its clinical behavior; however, morphologic and molecular evaluation allows categorization based on degree of differentiation, local invasion, and metastasis. Page 2 of 4 The above characteristics are only broad generalizations, and there are always exceptions. Metastasis is the only solid criteria of malignancy. 1- Differentiation and Anaplasia Differentiation refers to how closely tumor cells histologically (and functionally) resemble their normal cell counterparts Anaplasia refers to lack of differentiation. In general, neoplastic cells in benign lesions are well differentiated; cells in malignant neoplasms can range from well differentiated to completely undifferentiated. Well-differentiated tumors, whether benign or malignant, tend to retain the functional characteristics of their normal counterparts (e.g., hormone production by endocrine tumors or keratin production by squamous epithelial tumors). Malignant cells can revert to embryologic phenotypes or express proteins\ functional hormones not elaborated by the original cell of origin. Histologic changes in tumors (cytological features of malignancy) include the following: Pleomorphism: Variation in the shape and size of cells and/or nuclei Abnormal nuclear morphology: Darkly stained (hyperchromatic) nuclei with irregularly clumped chromatin, prominent nucleoli, and increased nuclear-to-cytoplasmic ratios (approaching 1:1 versus normal ratios of 1:4 or 1:6) Abundant and/or atypical mitoses reflecting increased proliferative activity and abnormal cell division (e.g., tripolar mitoses, so called Mercedes-Benz sign) Loss of polarity: Disturbed orientation and tendency for forming anarchic, disorganized masses Tumor giant cells with single polyploid nuclei or multiple nuclei Ischemic necrosis due to insufficient vascular supply. 2- Local Invasion Most benign tumors grow by expansion as cohesive, expansile masses that develop a surrounding rim of condensed connective tissue, or capsule. These tumors do not penetrate the capsule or the surrounding normal tissues, and the plane of cleavage between the capsule and the surrounding tissues facilitates surgical enucleation. Malignant neoplasms are typically invasive and infiltrative, destroying surrounding normal tissues. They commonly lack a well-defined capsule and cleavage plane, making simple excision impossible. Consequently, surgery requires removal of a considerable margin of healthy and apparently uninvolved tissue. 3- Metastasis Metastasis involves invasion of lymphatics, blood vessels, or body cavities by tumor, followed by transport and growth of secondary tumor cell masses discontinuous from the primary tumor. This is the single most important feature distinguishing benign from malignant. Page 3 of 4  Metastatic spread increases with lack of differentiation, local invasion, rapid growth, and large size. Almost all malignant tumors can metastasize; except for central nervous system (CNS) tumors and cutaneous basal cell carcinomas that rarely metastasize. Special forms of malignant tumors Occult carcinoma: it is the term given to carcinoma which manifests itself primarily as metastases because the original tumor is not sufficiently large to produce symptoms, e.g.: carcinoma of prostate, nasopharynx, maxillary antrum, and thyroid gland. Locally malignant tumors: they are malignant tumors which are locally invasive and destructive, but they do not give rise to distant metastases, e.g Basal cell carcinoma, Giant cell tumor of bone (osteoclastoma), carcinoid tumor of the appendix, and adamantinoma of the jaw. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9 th ed. Elsevier. Page 4 of 4  31 Types & Subdivisions and Communication in the nervous tissue ILOs By the end of this lecture, students will be able to 1. Describe the organization of the nervous system in relevance to its function. 2. Correlate the process of chemical transmission to function of synapses. 3. Explain the role of reflex arc in responding to a stimulus. 4. Compare between the somatic and autonomic reflex action. 5. Relate the reflex action to the body functions. Division of nervous system: (figure 1) Nervous system controls all the activities of the body. It is quicker than the other control system in the body namely, the endocrine system. The anatomical unit of the nervous system is the nerve cell or the neuron. The nervous system is divided into two parts namely: 1. Central nervous system 2. Peripheral nervous system 1) - Central nervous system (CNS): The central nervous system includes brain and spinal cord. It is formed of neurons and the supporting cells (neuroglia). The CNS processes many different kinds of incoming sensory information. It is also the source of thoughts, emotions, and memories. Most signals that stimulate muscles to contract and glands to secrete originate in the CNS. 2) - Peripheral nervous system (PNS): The peripheral nervous system is formed by the neurons and their processes present in all regions of the body. It consists of all nervous tissue outside the CNS. Neurons are capable of generating and transmitting electrochemical impulses. PNS consists of cranial nerves arising from the brain (Twelve pairs of cranial nerves emerge from the brain) and spinal nerves arising from the spinal cord (thirty-one pairs of spinal nerves emerge from the spinal cord). Each nerve follows a defined path and serves a specific region of the body. The peripheral nervous system relays information to and from the central nervous system. PNS is again divided into two subdivisions: a. Somatic nervous system b. Autonomic nervous system Somatic nervous system: Page 1 of 9 The somatic nervous system includes the nerves supplying the skeletal muscles. Thus, it controls the voluntary movement of the body by acting on skeletal muscles. It is also called the voluntary nervous system. Autonomic nervous system: The autonomic nervous system is concerned with regulation of visceral or vegetative functions, such as heart rate, blood pressure, digestion, temperature regulation, and reproductive function. So it is otherwise called vegetative or involuntary nervous system. The autonomic nervous system consists of two divisions: a. Sympathetic division b. Parasympathetic division In general, the sympathetic division helps support exercise or emergency actions, the “fight or-flight” responses, and the parasympathetic division takes care of “rest-and-digest” activities Figure 1: division of nervous system Comparison of somatic and autonomic nervous system: (table 1) The somatic nervous system includes both sensory and motor neurons. Sensory neurons convey input from receptors for somatic senses (tactile, thermal, pain, and proprioceptive sensations) and from receptors for the special senses (sight, hearing, taste, smell, and equilibrium). All of these sensations normally are consciously perceived. In turn, somatic motor neurons innervate skeletal muscles, the effectors of the somatic nervous system, and produce both reflexive and voluntary Page 2 of 9  movements. When a somatic motor neuron stimulates the muscle, it contracts; the effect always is excitation. If somatic motor neurons cease to stimulate a muscle, the result is a paralyzed muscle. Autonomic Nervous System The main input to the ANS comes from autonomic (visceral) sensory neurons. Mostly, these neurons are associated with sensory receptors located in blood vessels, visceral organs, muscles, and the nervous system that monitor conditions in the internal environment. Comparison of Somatic and Autonomic Motor Neurons The axon of a single, myelinated somatic motor neuron extends from the central nervous system (CNS) all the way to the skeletal muscle fibers in its motor unit. By contrast, most autonomic motor pathways consist of two motor neurons in series, that is, one following the other. The first neuron (preganglionic neuron) has its cell body in the CNS; its myelinated axon extends from the CNS to an autonomic ganglion (a ganglion is a collection of neuronal cell bodies in the PNS.) The cell body of the second neuron (postganglionic neuron) is also in that same autonomic ganglion; its unmyelinated axon extends directly from the ganglion to the effector (smooth muscle, cardiac muscle, or a gland). All somatic motor neurons release only acetylcholine (ACh) as their neurotransmitter, but autonomic motor neurons release either ACh or norepinephrine (NE). Table 1: Comparison of the somatic and autonomic nervous system: Somatic nervous system Autonomic nervous system Sensory input From somatic and special senses Mainly from visceral sensory receptors Control of motor Voluntary control from cerebral cortex, Involuntary control from output with contribution from basal ganglia, hypothalamus, limbic system, cerebellum, brain stem and spinal cord brain stem and spinal cord; limited control from cerebral cortex Motor neuron One neuron pathway: somatic motor Usually two-neuron pathway: pathway neurons extending from CNS synapse preganglionic neuron extending directly with effector from CNS synapse with postganglionic neuron in autonomic ganglia, and postganglionic neuron extending from ganglion synapse with visceral effector. Neurotransmitters All somatic motor neurons release only All preganglionic neurons acetylcholine (ACh) (sympathetic & parasympathetic) Page 3 of 9  release ACh. Most sympathetic postganglionic neurons release noradrenaline (NA). all postganglionic parasympathetic neurons and few sympathetic neurons release ACh Effectors Skeletal muscles Smooth muscles, cardiac muscles and glands Responses Excitation (contraction of skeletal Excitation or inhibition muscles) (contraction or relaxation of muscles, increased or decreased secretions of glands) Classification of nerve fibers: A) According to distribution: Nerve fibers are classified into two types on the basis of distribution: 1. Somatic nerve fibers which supply skeletal muscles of the body 2. Autonomic nerve fibers which supply the various internal organs of the body B) According to function: Functionally nerve fibers are of two types: 1. Motor nerve fibers: The motor nerve fibers carry motor impulses from the central nervous system to different parts of the body. These nerve fibers are also called the efferent nerve fibers. 2. Sensory nerve fibers: The sensory nerve fibers carry sensory impulses from different parts of the body to central nervous system. These nerve fibers are also known as afferent nerve fibers. C) According to structure: Depending upon the structure, the nerve fibers are classified into: 1. Myelinated nerve fibers: which are covered by myelin sheath 2. Non-Myelinated nerve fibers: these fibers do not have myelin sheath D) According to diameter and conduction(table 2) The nerve fibers are classified into 3 major types on the basis of thickness of the nerve fiber and the conduction velocity. The velocity of impulse through the nerve fiber is directly proportional to the thickness of the fibers. The different types of nerve fibers are given in table 2. Except C fibers, all nerve fibers are myelinated. Page 4 of 9  Table 2: types of nerve fibers Type Diameter Velocity of conduction (m/second) A Alpha (type I) 12-24 µ 70-120 Beta (type II) 6-12 µ 30-70 Gamma 5-6 µ 15-30 Delta (type III) 2-5 µ 12-15 B 1-2 µ 3-10 C (type IV) ≤1.5 µ 0.5-2 Neuromuscular and synaptic transmission Impulses are transmitted over chemical or electrical synapses linking one neuron (presynaptic cell) with another neuron, muscle, or gland (postsynaptic cell). At chemical synapses, an impulse in the presynaptic axon causes secretion of a chemical that diffuses across the 30- nm-wide (approximately) synaptic cleft and binds to receptors on the surface of the postsynaptic cell. This triggers events that open or close channels in the membrane of the postsynaptic cell, mediating excitation or inhibition. At electrical synapses, the membranes of the presynaptic and postsynaptic neurons are close together, and gap junctions form low resistance bridges through which ions pass with relative ease from one neuron to the next. General characteristics of chemical synapses 1. An action potential in the presynaptic cell causes depolarization of the presynaptic terminal. 2. As a result of the depolarization, Ca2+ enters the presynaptic terminal, causing release of neurotransmitter into the synaptic cleft. 3. Neurotransmitter diffuses across the synaptic cleft and combines with receptors on the postsynaptic cell membrane, causing a change in its permeability to ions and, consequently, a change in its membrane potential. 4. Inhibitory neurotransmitters hyperpolarize the postsynaptic membrane: excitatory neuro- transmitters depolarize the postsynaptic membrane. Neuromuscular junction (Figure 2) Is the synapse between axons of motor neurons and skeletal muscle. The neurotransmitter released from the presynaptic terminal is Acetylcholine (Ach) , and the postsynaptic membrane contains a nicotinic receptor. 1. Depolarization of the presynaptic terminal and Ca 2+ uptake Action potentials are conducted down the motor neuron. Depolarization of the presynaptic terminal opens Ca2+ channels. When Ca2+ permeability increases, Ca2+ rushes into the presynaptic terminal down its electrochemical gradient. 2. Ca2+ uptake causes release of ACh into the synaptic cleft The synaptic vesicles containing the Ach fuse with the plasma membrane and empty their contents into the cleft by exocytosis. Page 5 of 9 3. Diffusion of ACh to the postsynaptic membrane (muscle end plate) and binding of ACh to Acetylcholine (cholinergic) receptors. The ACh receptor is also a Na+ and K+ ion channel. Binding of Ach to α subunits of the receptor causes a conformational change that opens the central core of the channe land increases its conductance to Na and K.These are examples of ligand-gated channels. 4. End plate potential (EPP) in the postsynaptic membrane Because the channels opened by ACh conduct both Na+ and K+ ions, the postsynaptic membrane potential is depolarized to a value halfway between the Na+ and K+ equilibrium potentials (approximately 0 mV). The produced end plate potential (EPP)is not an action potential, but simply a depolarization of the specialized muscle end plate. 5. Depolarization of adjacent muscle membrane to threshold Once the end plate region is depolarized, local currents cause depolarization and action potentials in the adjacent muscle tissue. Action potentials in the muscle are followed by contraction. Degradation of Ach The EPP is transient because Ach is degraded to acetylCoA and choline by acetylcholinesterase (AChE) on the muscle end plate. One-half of the choline is taken back into the presynaptic ending by Na+-choline cotransport and used to synthesize new ACh. Figure 2: Neuromuscular junction Reflex arc and reflex action The basic unit of integrated reflex activity is the reflex arc. This arc consists of a sense organ (receptor), an afferent neuron, one or more synapses within a central integrating station (center), an efferent neuron, and an effector( Figure 3). Receptor; a specialized structure sensitive to changes inside or outside the body. It converts different forms of energy into nerve impulses. Page 6 of 9  Afferent neuron; it carries nerve impulses from receptor to the CNS. Center; inside the CNS. Efferent neuron; carries the impulses from center to the effector organ. In mammals, the connection between afferent and efferent somatic neurons is generally in the brain or spinal cord.The simplest reflex arc is one with a single synapse between the afferent and efferent neurons. Such arcs are monosynaptic, and reflexes occurring in them are called monosynaptic reflexes. Reflex arcs in which one or more interneuron is interposed between the afferent and efferent neurons are called polysynaptic reflexes. There can be anywhere from two to hundreds of synapses in a polysynaptic reflex arc. Figure 3; Reflex arc Monosynaptic reflexes: The stretch reflex (Figure 4) When a skeletal muscle with an intact nerve supply is stretched, it contracts. This response is called the stretch reflex. The stimulus that initiates the reflex is stretch of the muscle, and the response is contraction of the muscle being stretched. The stretch reflex is the best known and studied monosynaptic reflex and is typified by the knee jerk reflex. Figure 4: Stretch reflex Page 7 of 9 Polysynaptic reflexes: Withdrawal reflex (Figure 5)The withdrawal reflex is a typical polysynaptic reflex that occurs in response to a usually painful stimulation of the skin or subcutaneous tissues and muscle. The response is flexor muscle contraction and inhibition of extensor muscles, so that the body part stimulated is flexed and withdrawn from the stimulus. Figure 5: Withdrawal reflex Autonomic Reflex action: Stretch receptors in the bladder wall initiate a reflex contraction. Fibers in the pelvic nerves are the afferent limb of the voiding reflex, and the parasympathetic fibers to the bladder that constitute the efferent limb also travel in these nerves. The reflex is integrated in the sacral portion of the spinal cord. Peristalsis is a reflex response that is initiated when the gut wall is stretched by the contents of the lumen, and it occurs in all parts of the gastrointestinal tract from the esophagus to the rectum. These are examples of autonomic reflexes where the effector organ is under involuntary control (smooth muscle or a gland) Figure 6: Autonomic reflex action Page 8 of 9 Difference between Somatic and Autonomic reflex arcs Page 9 of 9  29 MECHANISMS OF CANCER SPREAD, GRADING AND STAGING ILOs By the end of this lecture, students will be able to 1. Delineate pathways of spread in relation to tumor subtypes 2. Correlate the tumor grading and staging to tumor prognosis Pathways of Cancer Spread : Cancer dissemination occurs by three routes:  Direct spread: To invade the nearby structures due to lack of a capsule. Lymphatic spread  Transports tumor cells to regional nodes (through lymphatic vessels at tumor margins) and ultimately throughout the body.  Lymph nodes draining tumors are frequently enlarged; this can result from metastatic tumor cell proliferation or from reactive hyperplasia as reaction to tumor antigens.  Biopsy of the proximal sentinel lymph node draining a tumor can allow accurate assessment of tumor metastasis (for purpose of tumor staging).  Carcinomas usually prefer metastasis by lymphatics prior to hematogenous spread. Hematogenous spread is typical of sarcomas but also is the favored route for certain carcinomas (e.g., renal). Because of their thinner walls, veins are more frequently invaded than arteries, and metastasis follows the pattern of venous flow; understandably, lung and liver are the most common sites of hematogenous metastases.  Seeding of body cavities and surfaces (Transcoelomic spread): occurs by dispersion into peritoneal, pleural pericardial, subarachnoid, or joint spaces. Ovarian carcinoma typically spreads transperitoneally to the surface of abdominal viscera, often without deeper invasion. Mucus-secreting appendiceal carcinomas can fill the peritoneum with a gelatinous neoplastic mass called pseudomyxoma peritonei. Perineural spread: Invades the nerves in the tissue. Clinically this presents as pain. Mechanism of spread: 1. Angiogenesis: In the absence of new vessels, tumor cannot access the vasculature so that angiogenesis also clearly influences metastatic potential. Tumors require nutrients and waste removal; thus they cannot enlarge beyond a 1- to 2-mm size without inducing host blood vessel growth (angiogenesis). New tumor vessels differ from normal vasculature by being dilated and leaky with slow and abnormal flow. Endothelial growth proteins include vascular endothelium growth factor (VEGF) and basic fibroblast growth factor (bFGF); proteases can also release preformed angiogenic mediators (e.g., bFGF) from the extracellular matrix (ECM). Page 1 of 4  2. Invasion and Metastasis: It involves the following steps: I. Invasion of Extracellular Matrix: To metastasize, tumor cells must dissociate from adjacent cells, and then degrade, adhere, and migrate through ECM. Detachment: Normal epithelial cells bind each other through adhesion molecules, called cadherins. In several carcinomas, there is downregulation of epithelial (E)-cadherins, thereby reducing cellular cohesion. ECM degradation: Tumors elaborate proteases or can induce stromal cell to produce them. Matrix metalloproteinase 9 (MMP9) degrades epithelial and vascular basement membrane type IV collagen, in addition to releasing ECM-sequestered pools of VEGF. ECM attachment: Invading cells must express adhesion molecules that allow interaction with the ECM. Migration: In addition to diminished adhesivity, tumor cells have increased locomotion. They also migrate in response to stromal cell chemotactic factors, degraded ECM components, and liberated stromal growth factors. II. Vascular Dissemination and Homing of Tumor Cells: Tumor cells embolize in the bloodstream as self-aggregates and by adhering to circulating leukocytes and platelet. Exactly where tumor cell emboli eventually lodge and begin growing is influenced by the following: 1) Vascular and lymphatic drainage from the site of the primary tumor. 2) Interaction with specific receptors. Certain tumor cells express adhesion molecules that bind high endothelial venules in lymph nodes. Other tumors exhibit specific chemokine receptors that interact with ligands uniquely expressed in certain vascular beds. 3) The microenvironment of the organ or site (e.g., a tissue rich in protease inhibitors might be resistant to penetration by tumor cells).  Grading and staging of malignant Tumors This assessment provides a semiquantitative estimate of the clinical gravity of a tumor. Both histologic grading and clinical staging are valuable for prognostication and for planning therapy, although staging has proved to be of greater clinical value. Grading is based on the degree of differentiation of malignant tumor (how much the tumor resembles its normal counterpart). It depends on architectural features and\or number of mitoses. Grading is evaluated by histological examination of malignant tissue. Tumors are classified into;  Grade I: well differentiated: contains 75% or more of well differentiated tumor cells. (Lower grade, slower growth rate and radioresistant)  Grade II: moderately differentiated: contains 25-75% differentiated tumor cells.  Grade III: poorly differentiated: contains less than 25% tumor cells. (Higher grade, Rapidly growing and is radiosensitive). Staging is based on the extent of local and distant spread. The major system currently used is the American Joint Committee on Cancer (AJCC) staging; the classification involves a TNM designation: Page 2 of 4   T for tumor (size and local invasion)  N for regional lymph node involvement  M for distant metastases.  Staging is a clinical procedure depending on clinical, radiological and sometimes histological evaluation. Diagnosis of neoplasia: 1. Clinically 2. Radiological methods: CT- PET -CT, Ultrasound, MRI, Mammogram, and others. 3. Laboratory  Clinical Aspects of Neoplasia Although malignant tumors are more threatening than benign, any tumor can cause morbidity and mortality. Local Effects Tumors of the GI tract may cause obstruction of the bowel or may ulcerate and cause bleeding, or pain. Cancer Cachexia: Loss of body fat, lean body mass, and profound weakness. It is multifactorial but is largely driven by TNF and other cytokines elaborated by inflammatory cells in response to tumors which lead to: Loss of appetite Reduced synthesis and storage of fat and increased mobilization of fatty acids from adipocytes Increase catabolism of muscle and adipose tissue. Paraneoplastic syndrome\ Hormone production: Malignant tumors may acquire the ability to elaborate hormone-like substances giving rise to aberrant hormonal effects such as hypoglycaemia (insulin production) or hypercalcemia (parathyroid hormone [PTH]-producing tumors).  Laboratory Diagnosis of Cancer 1- Histologic and Cytologic Methods  Histologic examination is the most important method of diagnosis. In addition to traditional formalin-fixed and paraffin-embedded sections, quick-frozen sections provide rapid diagnoses during procedures.  Cytologic interpretation is based chiefly on changes in the appearance of individual cells.  Screening (Pap) smears involve examination of shed cells; exfoliative cytologic examination is used most commonly in the diagnosis of cancer of the uterine cervix.  Fine-needle aspiration involves aspiration of cells and fluids from tumors or masses. Page 3 of 4 1- Tumor markers: Tumor markers are tumor-derived or - associated molecules (antigens) that are detected in tumor tissues, blood or other body fluids. Examples and clinical applications: Prostate-specific antigen (PSA) elaborated by prostate epithelium; elevated levels can reflect malignancy. 2- Molecular methods: Prognosis of malignancy: Certain genetic alterations are associated with poor prognosis; identification of these can stratify treatment. HER-2-NEU overexpression in breast cancer is an indication for monoclonal antibody therapy against epithelial growth factor receptor. Detection of residual disease: The ability to detect extremely small numbers of malignant cells can be useful for evaluating therapy efficacy or for assessing tumor recurrence. Diagnosis of hereditary predisposition to cancers: e.g., predisposition to breast cancer can be detected by analysis of BRCA-1, BRCA-2 allowing family screening and risk stratification. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 4 of 4  1 L 30 Types, distribution & function of muscular tissue ILOs By the end of this lecture, students will be able to 1. Correlate type of muscular tissue to its structure & function. 2. Correlate structural adaptation of smooth muscle to its function. 3. Interpret response of smooth muscles structurally to different stress stimuli in health & disease Types of muscle tissue There are three types of muscle tissue: 1. Skeletal (voluntary) muscle 2. Cardiac (involuntary) muscle 3. Smooth(involuntary) muscle The common feature between the three types is their ability for contraction because of their cytoskeleton components of contractile myofilaments, in response to nerve stimulation. Some special terms are used when describing muscle tissue: cytoplasm is referred to as sarcoplasm, cell membrane is sarcolemma and smooth endoplasmic reticulum is sarcoplasmic reticulum. The smooth muscle ⮚ Site; wall of visceral organs such as, blood vessels, gastrointestinal tube, urinary tract (ureter & urinary bladder) and respiratory passages (bronchi & bronchioles). ⮚ Light microscopic features: a) Shape; In a longitudinal cut section, Smooth muscle fibers are fusiform, elongated cells that taper at either ends. In a transverse section, cells appear rounded with different diameters according to level of cut section. (Fig 1) b) Nucleus; single and central oval nucleus housing two or more nucleoli (What does this indicate?). During muscle shortening, the nucleus assumes a characteristic "corkscrew appearance," as a result of the method of smooth muscle contraction c) Sarcoplasm; homogenous esinophilic on staining with H & E. d) Each smooth muscle cell is surrounded by an external lamina, which invariably separates the sarcolemma of contiguous muscle cells. Embedded in the external lamina are 1  2 numerous reticular fibers, which appear to envelop individual smooth muscle cells and function in harnessing the force of contraction. Figure 1. Sites and organization of smooth muscle cells L.S. T.S. ⮚ Structural organization (Fig 2) a) In wall of visceral organs, smooth muscle cells are arranged in two perpendicular layers, as in the digestive and urinary systems. This arrangement permits waves of peristalsis. b) In each layer smooth muscles are arranged in the same direction, in an interdigitating pattern. Fig 2. ⮚ Ultra-structure (Fig 3) The perinuclear cytoplasm of smooth muscle cells, especially the regions adjacent to the two poles of the nucleus, contains numerous mitochondria, Golgi apparatus (WHY?), rough 2  3 endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER), and inclusions such as glycogen. Contractile myofilaments are of two types; Thin myofilaments; actin (microfilaments) & tropomyosin, thick myofilaments; myosin. They are arranged in bundles so that thin myofilaments are at the peripheral part & thick myosin filaments are in the central region, allowing overlapping of both types. Desmin intermediate filaments form a network to transmit contractile action between the muscle bundles. Fig Dense bodies; are formed of an anchoring protein that fixes one end of actin myofilaments and desmin. Bundles of myofilaments are oriented in different directions, thus lacking regular registration encountered in the skeletal muscle. This explains smooth appearance (non- striated) of sarcoplasm under the microscope. (Fig 3) Structural adaptation to function: a) Excitation contraction coupling; transmission of electrical activity generated on the sarcolemma upon nervous stimulation is through shallow invaginations of the sarcolemma called caveolae. In turn, caveolae are associated with profiles of SER to release the stored Calcium ions into the sarcoplasm to initiate contraction. b) Innervation: Most types of Smooth muscle cells, such as in wall of blood vessels, are not innervated individually, where nerve fibers synapse with only few smooth muscles. The neural component of the synapse is the en passant type, which occurs as axonal swellings that contain synaptic vesicles, housing either norepinephrine for sympathetic innervation or acetylcholine for parasympathetic innervation. c) Smooth muscle cells are connected to each other through gap junctions, so as to transmit nerve impulses rapidly between the cells.(Fig 3) d) Smooth muscles contract also in response to hormonal stimulation, such as oxytocin that acts on uterine smooth muscle. e) In addition to its contractile functions, some smooth muscle is capable of exogenous protein synthesis. Among the substances manufactured by smooth muscle cells for extracellular utilization are collagen, elastin, glycosaminoglycans, proteoglycans, and growth factors. Response of smooth muscle to stress Smooth muscle cells retain their mitotic capability to form more smooth muscle cells. This ability is especially evident in the pregnant uterus, where the muscular wall becomes thicker both by hypertrophy of individual cells and by hyperplasia derived from mitotic activity of the smooth muscle cells. Small defects, subsequent to injury, may result in formation of new smooth muscle cells. These new cells may be derived via mitotic activity of existing smooth muscle cells, as in the 3  4 gastrointestinal and urinary tracts, or from differentiation of relatively undifferentiated pericytes accompanying some blood vessels. Fig 3. Ultra structure Smooth muscle innervation Smoot muscle contraction 4  1 1 The Covering of Epithelium ILOs By the end of this lecture, students will be able to 1. Interpret the significance of general features of epithelium in relevance to its functional requirements. 2. Correlate structural adaptation of each type of epithelium to its function. 3. Recognize significance of epithelial in view of its structure & function. Epithelial tissue Epithelial tissue is present in two forms: (1) as sheets of contiguous cells (epithelia) that cover the body on its external surface and line the hollow organs on the internal surface, and (2) as glands, which originate from invaginated epithelial cells. Epithelial tissues have numerous functions Protection of underlying tissues of the body from abrasion and injury. Transcellular transport of molecules across epithelial layers. Secretion of mucus, hormones, enzymes, and so forth, from various glands. Absorption of material from a lumen (e.g., intestinal tract or certain kidney tubules). Control of movement of materials between body compartments via selective permeability of intercellular junctions between epithelial cells. Detection of sensations via taste buds, retina of the eye, and specialized hair cells in the ear. General features of epithelium 1. It is formed of closely packed cells with limited intercellular spaces. 2. The cells are related by intercellular junctions. 3. They are separated from the underlying connective tissue by an extracellular matrix, the basal lamina. 4. It has a high regenerative capacity through stem cells division. Epithelia possess a unipotent stem cell that is capable of division and differentiation to one type of epithelium only. 5. It is a non-vascular tissue but richly innervated. 6. The adjacent supporting connective tissue through its capillary beds supplies nourishment and oxygen via diffusion through the basal lamina. 1 Classification of Epithelial Membranes 2 Cell arrangement and morphology are the bases of classification of epithelium Simple; formed of a single cell layer. Stratified; formed of several cell layers. Types Shape of cell Site Function I- Simple 1. Squamous Flat cells forming thin Lining: pulmonary Limiting membrane, sheets alveoli, blood and fluid transport, lymphatic vessels. gaseous exchange. 2. Cuboidal Cuboidal Lining :Thyroid gland Secretion, absorption,