General Pathology: Inflammation And Repair PDF

PATHOLOGY LDCU MEDICINE-2 Dr. Casio & Dr. Rana GENERAL PATHOLOGY: INFLAMMATION AND REPAIR INFLAMMATION HARMFUL CONSEQUENCE(S) OF INFLAMMATION ...

PATHOLOGY LDCU MEDICINE-2 Dr. Casio & Dr. Rana GENERAL PATHOLOGY: INFLAMMATION AND REPAIR INFLAMMATION HARMFUL CONSEQUENCE(S) OF INFLAMMATION  Inflammation is a response of vascularized tissues to  Example: Pain, Functional Impairment infections and damaged tissues that brings cells and  Typically, self limited (resolves as inflammation abates) molecules of host defense from the circulation to the sites  If inflammation is misdirected /not controlled properly, it will where they are needed, in order to eliminate the offending cause diseases such as agents. o Autoimmune diseases (e.g. SLE, Graves Disease)  Although in common medical and lay parlance, o Against normally harmless environmental inflammation suggests a harmful reaction, it is actually a substances (Allergies) protective response that is essential for survival. o Get rid the cause of initial injury (e.g. initial pain reflex, constriction vessels to limit bleeding, fight microbes) o Get rid the consequence of such injury (e.g. tissue damage, dissolution of clots) o Without inflammation, infections would go unchecked, wounds never heal, injured tissues remain. STEPS OF INFLAMMATORY RESPONSE 1. Recognition of the injurious agent ◦ The injurious agent is located extravascular ◦ Recognition is done by host cells and molecules 2. Recruitment of leukocytes ◦ WBC and plasma proteins are recruited from the LOCAL AND SYSTEMIC INFLAMMATION vessel to the site of injury (extravascular)  Most of the time, inflammation is LOCALIZED. 3. Removal of the agent  At times, inflammation localized but with systemic ◦ WBC and plasma proteins are ACTIVATED to manifestations like fever destroy the injuring agent  Rarely, it is systemic like in cases of disseminated bacterial 4. Regulation (control) of the response infection ◦ Activation of WBC and plasma proteins are  The inflammatory reaction is called sepsis TERMINATED 5. Resolution LOCAL RESPONSE ◦ Damaged tissue is repaired  📖 Largely confined to the site of infection or damage SYSTEMIC RESPONSE  🔎 A serious condition in which there is inflammation throughout the whole body. It may be caused by a severe bacterial infection (sepsis), trauma, or pancreatitis.  Sepsis is NOT A DIAGNOSIS but a form of Systemic Inflammatory Response Syndrome (SIRS) MEDIATORS OF INFLAMMATION  Are soluble substances produced by various inflammatory cells or as derivatives of plasma proteins. HISTORIC  Purpose: initiate and regulate reactions COMPONENTS OF INFLAMMATORY RESPONSE  Examples: Major Participants in the Inflammatory Reaction in Tissues o Prostaglandins by Mast cells and leukocytes 1. Blood vessels causing pain, fever and vasodilation ◦ Dilate to slow blood flow o Chemokines produced by leukocytes and mast ◦ Increase permeability to enable SELECTED cells cause chemotaxis and leukocyte activation proteins to go to site of injury o Complement, derivative of plasma produced in 2. Leukocytes liver causes direct bacterial/viral killing ◦ Initially within the vessel but becomes o Kinins derivative of plasma produced in liver activated then migrate outside to the site of causes pain, increased vascular permeability injury to eliminate agent of injury SAAPL | MD 2024 1  ACUTE VS. CHRONIC INFLAMMATION o In 1973, he noted that inflammation is not a disease but a stereotypic response that has a salutary effect on its host FEATURE ACUTE CHRONIC  Julius Cohnheim o “There is no inflammation WITHOUT the Onset Fast; minutes Slow; days to hours participation of blood vessels”  Elie Metchnikoff Cellular Mainly Monocytes/macrophages o Discovered the process of phagocytosis infiltrate Neutrophils and lymphocytes o Concluded that the purpose of inflammation was to bring phagocytic cells to the injured area to Tissue injury, Usually mild Often severe and engulf invading bacteria fibrosis and self-limited progressive  Sir Tomas Lewis Local and Prominent Less o Established the concept that chemical systemic substances, such as histamine (produced locally signs in response to injury), mediate the vascular changes of inflammation ACUTE INFLAMMATION  Initial rapid response CAUSES OF INFLAMMATION  More of a response as part of Innate Immunity 1. Infections (microbial toxin- among most common)  Main characteristics: 2. Tissue necrosis (trauma, ischemia, physical and chemical o (1) Edema which is the exudation of fluid and injury) plasma proteins to tissues 3. Foreign bodies (urate crystal deposition in gout, lipid in o (2) Emigration of ACTIVATED leukocytes atherosclerosis) (mostly PMN/neutrophils) to tissues 4. Immune reactions (hypersensitivity, autoimmune disease)  📖 More prominent in the reactions of the innate immunity RECOGNITION OF MICROBES  📖 Inflammation is resolved IF the acute achieves its desire  Recognition of the offending agent – goal of eliminating the offenders o is the first step in all inflammatory reactions  📖 If the response fails to clear the stimulus, the reaction o actually done by the receptor can progress to a protracted phase that is called chronic  Receptors and circulating proteins are capable of inflammation recognizing (1) microbes, (2) products of cell damage  After recognition, it triggers inflammation CHRONIC INFLAMMATION  Receptors are usually seen in:  Protracted phase if acute inflammatory response fails to o Plasma membrane for extracellular microbes stop stimulus o Endosomes for ingested microbes  Longer in duration o Cytosol for intracellular microbes  Associated with more tissue destruction  Main characteristics include: CELLULAR RECEPTORS FOR MICROBES o Presence of lymphocytes & macrophages  Seen at plasma membrane, endosomes and cytosol. Proliferation of blood vessels  Express in different variety of cells: Epithelial cells, dendritic o Deposition of connective tissue cells, leukocytes.  More of a response as part of Adaptive Immunity  Best example: Toll Like receptor (TLR)  Engagement of microbes to these receptors trigger 📖 HISTORICAL HIGHLIGHTS ABOUT INFLAMMATION production of molecules that initiates the inflammatory  Egyptian papyrus dated around 3000 BC process. o Earliest reference to inflammation in ancient medical literature  Celsus o Roman writer of the 1st century AD o First listed the four cardinal signs of inflammation  Rubor (redness)  Tumor (swelling)  Calor (heat)  Dolor (pain)  Rudolf Virchow o Added the fifth clinical sign of inflammation, function laesa (loss of function), in the 19th century  John Hunter SAAPL | MD 2024 1 SENSORS OF CELL DAMAGE  ALL cells have cytosolic receptors that recognize molecules that are produced as a result of cell damage  detects the damage cells or its molecules or byproducts  Examples of cell damaged-molecules: o Uric acid molecules produced by breakdown of DNA o ATP molecules produced by damaged mitochondria o Reduced intracellular K concentration due to loss of ion from leaking outside of plasma membrane  Upon detection of cell damage molecules, the receptors REACTIONS OF BLOOD VESSELS IN ACUTE activate the Inflammasome INFLAMMATION  Inflammasome is a multiprotein cytosolic complex  The vascular reactions of acute inflammation consist of  Inflammasome Function: induces the production of o changes in the flow of blood cytokine- Interleukin 1 that results to leukocyte recruitment o permeability of vessels and triggers inflammation  Purpose: to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of OTHER RECEPTORS infection or injury.  Fc Tails of Leukocytes o Recognized microbes coated with antibodies o Recognized microbes coated with complements o Promotes ingestion, destruction of microbes and further inflammation. EXUDATE VS. TRANSUDATE  Exudation- escape of fluid from vascular to interstitial tissues or body cavities due to increase permeability of vessels. o extravascular fluid, CIRCULATING PROTEINS high protein containing  Mannose Binding Lectin (MBL)- Is a CIRCULATING cellular debris protein that recognizes microbial SUGARS and promotes  Transudate- is due to osmotic ingestion of the microbes and activation of complement or hydrostatic imbalance across system. vessel wall (no increase in permeability) o Low protein (mostly albumin) Acute Inflammation  Edema- excess of fluid to interstitial space Acute inflammation has three major components: o Can be exudate or transudate 1. Dilation of small vessels leading to an increase in blood  Pus – is a purulent exudate flow 2. Increased permeability of the microvasculature enabling plasma proteins and leukocytes to leave the circulation 3. Emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent SAAPL | MD 2024 1  CONTRACTION OF ENDOTHELIAL CELLS RESULTING IN INCREASED INTERENDOTHELIAL SPACES In the normal setting, the spaces between endothelial cells of the vessels are tight enough for the leukocytes and plasma proteins not to penetrate outside the vessels. CHANGES IN VASCULAR FLOW CALIBER  Vasodilation- is induced by chemical mediators on vascular smooth muscle. o most notably Histamine  📖 Most common mechanism of vascular leakage o One of earliest manifestations o First involves arterioles  📖 Elicited by histamine, bradykinin, leukotrienes & other o Results to increase blood flow manifested as chemical mediators redness.  📖 Also called the immediate transient response because it  STASIS- condition caused by engorgement of small blood occurs rapidly after exposure to the mediator & is usually vessels secondary to slowly moving of cells short-lived (15-30 minutes) o Example: Vascular congestion  📖 In some forms of mild injury, vascular leakage begins o If prolonged may trigger exudation after a delay of 2-12 hours & lasts for several hours or even  Increased vascular permeability is induced by histamine, days. Delayed prolonged leakage (seen in late-appearing kinins, and other mediators that produce gaps between sunburn). endothelial cells, by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the ENDOTHELIAL INJURY endothelium.  📖 Results in endothelial cell necrosis & detachment  📖 Direct damage to the endothelium is encountered in severe injuries or is induced by the action of microbes & microbial toxins that target endothelial cells  📖 Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells amplifying the reaction  📖 In most instances, leakage starts immediately after injury & is sustained for several hours until the damaged vessels are thrombosed or repaired Increased vascular permeability in inflammation (Vascular Leakage) INCREASED TRANSCYTOSIS  Several mechanisms are responsible for the increased  Vesicular transport of fluids across the cytoplasm may permeability of post capillary venules, a hallmark of acute occur under the influence of vascular endothelial growth inflammation: factor (VEGF) o Contraction of endothelial cells  VEGF o Endothelial Injury  Also causes increased leakiness of newly formed blood o Increased transcytosis vessels in the granulation tissue & chronic inflammation SAAPL | MD 2024 1 LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION Sialyl-Lewis X  The changes in blood flow and vascular permeability are (e.g., CLA) on Endothelium quickly followed by an influx of leukocytes into the tissue. glycoproteins; activated by E-selectin expressed on  The journey of leukocytes from the vessel lumen to the cytokines (CD62E) neutrophils, tissue is a multistep process that is mediated and controlled (TNF, monocytes, T by adhesion molecules and cytokines called chemokines. IL-1) cells (effector,  📖 The most important WBCs in inflammatory reactions are memory) the ones capable of phagocytosis: Sialyl-Lewis X Endothelium o Neutrophils on PSGL-1 and activated by o Macrophages other cytokines  Phagocytes ingest & destroy bacteria + other microbes + glycoproteins; P-selectin (TNF, necrotic tissue & foreign substances expressed on (CD62P) IL-1), neutrophils,  WBCs also produce growth factors that aid in repair histamine, or monocytes, T o If strongly activated, WBCs may induce tissue thrombin; cells (effector, damage & prolong inflammation because the platelets memory) WBC products that destroy microbes & help “clean ICAM-1 up” necrotic tissues can also injure normal Neutrophils, (CD54), ICAM- bystander host tissues. monocytes, 2 (CD102); LFA-1 T cells expressed on MULTISTEP PROCESS OF LEUKOCYTE MIGRATION (CD11aCD18) (naïve, endothelium effector, (upregulated memory on activated endothelium) ICAM-1 (CD54), ICAM- 2 (CD102); MAC-1 Monocytes, expressed on (CD11bCD18) DCs endothelium (upregulated on activated endothelium) Integrin VCAM-1  📖 The journey of WBCs from the vessel lumen to the tissue (CD106); is a multistep process that is mediated & controlled by Monocytes expressed on adhesion molecules & cytokines called chemokines T cells VLA-4 endothelium (naïve,  📖 Includes several steps: (CD49aCD29) (upregulated effector, o In the lumen: margination, rolling & adhesion to on memory) endothelium activated  Vascular endothelium in its normal, endothelium) unactivated state does not bind VCAM-1 (CD106), circulating cells or impede their passage Monocytes MAdCAM-1;  In inflammation, the endothelium is T cells (gut expressed on activated & can bind WBCs as a prelude α4β7 homing endothelium in to their exit from the blood vessels (CD49DCD29) naïve gut and gut- o Migration across the endothelium & vessel Wall effector, associated o Migration in the tissues toward a chemotactic memory) lymphoid stimulus tissues Endothelial CD31 SELECTINS AND INTEGRINS Ig CD31 cells, (homotypic Endothelial and Leukocyte Adhesion Molecules leukocytes interaction) Family Molecule Distribution Ligand CLA, Cutaneous lymphocyte antigen-1; GlyCAM-1, glycan- Sialyl-Lewis bearing cell adhesion molecule-1; HEV, high endothelial Neutrophils, venule; ICAM, intercellular adhesion molecule; Ig, X/PNAd on monocytes immunoglobulin; GlyCAM-1, T cells IL-1, interleukin-1; MAdCAM-1, mucosal adhesion cell CD34, L-selectin (naïve and adhesion molecule-1; PSGL-1, P-selectin glycoprotein Selectin MAdCAM-1, (CD62L central ligand-1; TNF, tumor necrosis factor; VCAM, vascular cell others; memory) adhesion expressed on B cells molecule. endothelium (naïve) (HEV) SAAPL | MD 2024 1 CHEMOTAXIS AND ITS INHIBITORS Local: endothelial Macrophages, activation (expression Cytokines endothelial of adhesion molecules). (TNF, cells, Systemic: fever, IL-1, IL-6) mast cells metabolic abnormalities, hypotension (shock) Leukocytes, Chemotaxis, leukocyte Chemokines activated activation macrophages Vasodilation, increased vascular permeability, Platelet- Leukocytes, leukocyte adhesion, activating mast chemotaxis, factor cells degranulation, oxidative burst Leukocyte chemotaxis and *insert text here* Plasma activation, direct target Complement (produced killing (membrane PHAGOCYTOSIS in liver) attack Phagocytosis involves three sequential steps complex), vasodilation 1. Recognition and attachment of the particle to be (mast cell stimulation) ingested by the leukocyte; Increased vascular Plasma 2. Engulfment, with subsequent formation of a phagocytic permeability, smooth Kinins (produced muscle contraction, vacuole in liver) vasodilation, pain 3. Killing or degradation of the ingested material. Role of Mediators in Different Reactions of Inflammation PHAGOCYTIC RECEPTORS Reaction of Principal Mediators 1.Mannose receptors- that binds to sugars found in Inflammation microbial cell wall allowing recognition of microbes. Vasodilation Histamine 2. Scavenger receptor- mediate endocytosis of oxidized Prostaglandins LDL particles of microbes Increased Histamine vascular C3a and C5a (by liberating vasoactive permeability amines from mast cells, other cells) Leukotrienes C4, D4, E4 Chemotaxis, TNF, IL-1 leukocyte Chemokines recruitment and C3a, C5a activation Leukotriene B4 Fever IL-1, TNF Prostaglandins Pain Prostaglandins Bradykinin Tissue damage Lysosomal enzymes of leukocytes Reactive oxygen species CYTOKINES IN INFLAMMATION IN ACUTE INFLAMMATION TNF Macrophages, Stimulates expression of MEDIATORS OF INFLAMMATION endothelial adhesion molecules and secretion Principal Mediators of Inflammation of other cytokines; Mediator Source Action systemic effects. Mast cells, Vasodilation, increased IL-1 Macrophages, Similar to TNF; greater Histamine basophils, vascular permeability, endothelial role platelets endothelial activation cells, in fever Mast cells, some epithelial Prostaglandins Vasodilation, pain, fever leukocytes cells Increased vascular IL-6 Macrophages, Systemic effects (acute Mast cells, permeability, other cells phase Leukotrienes leukocytes chemotaxis, leukocyte response) adhesion, and activation SAAPL | MD 2024 1  Chemokines Macrophages, Recruitment of endothelial leukocytes to cells, sites of inflammation; T lymphocytes, migration of cells in mast cells, normal tissues other cell types IL-17 T lymphocytes Recruitment of neutrophils and monocytes IN CHRONIC INFLAMMATION IL-12 Dendritic cells, Increased production of macrophages IFN-γ IFN-γ T lymphocytes, Activation of NK cells macrophages Morphologic Patterns of Acute Inflammation (increased ability to kill  Serous Inflammation- exudation of cell poor fluid. microbes and tumor cells) o Example: skin blister in burns. IL-17 T lymphocytes Recruitment of  Fibrinous Inflammation- there is procoagulant stimulus. neutrophils Seen in lining of body cavities such as meninges, and monocytes pericardium or pleura. The most important cytokines involved in inflammatory  Purulent (suppurative) inflammation- production of pus reactions are listed. Many other cytokines may play lesser which is an exudate containing more cells (neutrophils), roles in inflammation. There is also considerable overlap between the cytokines involved in acute and chronic tissue debris and edema fluid. inflammation. Specifically, all the cytokines listed under  Ulcers- local defect or excavation of the surface of organ or acute inflammation may also contribute to chronic tissue produced by sloughing of inflamed necrotic tissue. inflammatory reactions. IFN-γ, Interferon-γ; IL-1, interleukin- 1; NK, natural killer; TNF, tumor necrosis factor. CHRONIC INFLAMMATION  Chronic inflammation is a response of prolonged duration Complement System (weeks or months) in which inflammation, tissue injury and  One of the important contributors on inflammation, which attempts at repair coexist, in varying combinations. are collection of soluble proteins and membrane receptors present in our blood.  Functions to protect the body against o Microbes o Any other pathologic conditions  Critical step in Complement Activation: Protealysis or cleavage of C3 which can occur or triggers in any of the 3 pathways which are the inflammation, phagocytosis and lysis of the microbes. Causes of Chronic Inflammation  Persistent infections- microorganisms that are difficult to THE COMPLEMENT SYSTEM HAS 3 PATHWAYS: eradicate (ex. mycobacteria, fungi)  Classicl pathway  Delayed type hypersensitivity reaction, granulomatous o recognizes antigen-antibody complexes reaction, chronic lung abscess o triggered by the fixation of C1 or the  Hypersensitivity diseases- autoimmune diseases COMPLIMENT 1 to the antibody, it could be the (rheumatoid arthritis, multiple sclerosis), allergic diseases IgG or IgM, that has combined with an antigen.  Prolonged exposure to potentially toxic agents- silica in  Alternative pathway silicosis, atherosclerosis by prolonged deposition of o Recognizes pathogen’s/ microbial surface cholesterol in arteries. molecules o The compliment can detect when there is an Morphologic Features of Chronic Inflammation endotoxin or lipopolysaccharide or anything such Chronic inflammation is characterized by: as the cobra venum or any foreign substance 1. Infiltration with mononuclear cells (macrophages, without the help of any antibodies. lymphocytes, plasma cells)  Lectin pathway – 2. Tissue destruction- due to persistence of offending o where mannose-binding lectin is recognizing agent microbial sugar (mannose) on the pathogen’s 3. Attempts at healing- by connective tissue replacement surface promoting ingestion of the microbes & of damaged tissue, accomplished by angiogenesis activation of the complement system (proliferation of small blood vessels) and fibrosis. SAAPL | MD 2024 1  Noncaseating granulomas Unknown Sarcoidosis with abundant activated etiology macrophages Immune Crohn reaction Occasional noncaseating disease against granulomas in the wall of (inflammatory undefined gut the intestine, with dense bowel microbes and, chronic inflammatory disease) possibly, self infiltrate A. Chronic inflammation in the lung B. In contrast, in antigens acute inflammation of the lung Systemic Effects of Inflammation Granulomatous Inflammation  Fever- IL-1 and TNF  A form of chronic inflammation characterized by collections o Bacterial products- LPS (lipopolysaccharides) are of activated macrophages often with T lymphocytes and exogenous pyrogens sometimes associated with central necrosis.  Acute Phase Proteins- mostly synthesize by liver  Granuloma formation is a cellular attempt to contain an o CRP, fibrinogen, serum amyloid, hepcidin (an iron offending agent that is difficult to eradicate. regulating peptide)  Some activated macrophages may fuse forming giant cells. o ESR (Erythrocyte Sedimentation Rate)- simple test for inflammatory response  Leukocytosis- occurs initially due accelerate release of cells from bone marrow (rise of more immature cells- band forms or left shift) Cell and Tissue Regeneration  The regeneration of injured cells and tissues involves cell proliferation, which is driven by growth factors and is critically dependent on the integrity of the extracellular matrix, and by the development of mature cells from stem cells. Examples of Diseases With Granulomatous Inflammation  The ability of tissues to repair themselves is determined, in Disease Cause Tissue Reaction part, by their intrinsic proliferative capacity. Caseating granuloma  Based on this criterion, the tissues of the body are divided (tubercle): focus of into three groups: activated macrophages 1. Labile (continuously dividing) tissues (epithelioid cells), rimmed 2. Stable tissues. Mycobacterium by fibroblasts, 3. Permanent tissues. Tuberculosis tuberculosis lymphocytes, histiocytes,  If repair cannot be accomplished by regeneration alone it occasional Langhans giant occurs by replacement of the injured cells with connective cells; central necrosis with tissue, leading to the formation of a scar, or by a amorphous granular debris; acid-fast bacilli combination of regeneration of some residual cells and scar Acid-fast bacilli in formation. Mycobacterium Leprosy macrophages; leprae TISSUE REPAIR noncaseating granulomas Gumma: microscopic to  Repair, also called healing, refers to the restoration of grossly visible lesion, tissue architecture and function after an injury. enclosing wall of repair is used for parenchymal and Treponema macrophages; plasma cell connective tissues and healing for surface Syphilis pallidum infiltrate; central cells are epithelia, but these distinctions are not based necrotic without loss of on biology, and we use the terms cellular outline; organisms interchangeably difficult to identify in tissue Rounded or stellate REPAIR OF DAMAGED TISSUES OCCURS BY TWO granuloma containing PROCESSES: Cat-scratch Gram-negative central granular debris disease bacillus and recognizable  Regeneration, which restores normal cells. neutrophils; giant cells o cells here have the capacity to proliferate uncommon o cell essentially return to normal state  Scarring or Connective Tissue Deposition SAAPL | MD 2024 1  o Cells are not capable to proliferate Cell and Tissue Regeneration o Tissue too severely injured.  The regeneration of injured cells and tissues involves: o Cell proliferation  is driven by growth factors  is critically dependent on the integrity of the ECM  Development of mature cells from tissue stem cells CELL PROLIFERATION: SIGNALS AND CONTROL MECHANISM  The ability of tissues to repair themselves is determined, in part, by their intrinsic proliferative capacity and the presence of tissue stem cells.  Based on these criteria, the tissues of the body are divided into three groups: 1. Labile (continuously dividing) tissues. are continuously being lost and replaced by maturation from tissue stem cells and by proliferation of mature cells. Example: Blood cells and skin. readily regenerate after injury as long as the pool of stem cells is preserved 2. Stable tissues are quiescent (in the G0 stage of the cell cycle) and have only minimal proliferative FIBROSIS activity.  Is a scarring process Capable of dividing in response to injury  is the deposition of collagen that occurs in the lungs, liver, Liver, kidney pancreas, fibroblast, kidney, and other organs as a consequence of chronic endothelial cells, smooth muscle 3. Permanent tissues inflammation or in the myocardium after extensive ischemic terminally differentiated and necrosis (infarction). nonproliferative in postnatal life. neurons and cardiac muscle, skeletal muscle Repair is through scar formation  📖 If the injured tissues are incapable of complete restitution, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of  Cell proliferation is driven by signals provided by growth connective (fibrous) tissue, a process that may result in factors and from the ECM. formation of a scar.  Growth factors are typically produced by cells near the site  📖 Although the fibrous scar is not normal, it provides of damage. enough structural stability that the injured tissue is usually  The most important sources of these growth factors are able to function. macrophages that are activated by the tissue injury, but epithelial and stromal cells also produce some of these  ORGANIZATION factors. o Is a kind of fibrosis developing in a tissue space occupied by an inflammatory exudate. o Example: organizing pneumonia affecting the lung SAAPL | MD 2024 1 MECHANISMS OF TISSUE REGENERATION 3. Formation of granulation tissue  Liver Regeneration o Migration and proliferation of fibroblasts and o The human liver has a remarkable capacity to deposition of loose connective tissue, together regenerate. with the vessels and interspersed mononuclear  Regeneration of the liver occurs by two major mechanisms: leukocytes, form granulation tissue (depends on the nature of the injury.) 4. Deposition of connective tissue o PROLIFERATION OF REMAINING o Granulation tissue is progressively replaced by HEPATOCYTES deposition of collagen. The amount of connective  Resection up to 90% of the liver can be tissue increases in the granulation tissue, corrected by proliferation of the residual eventually resulting in the formation of a stable hepatocytes. fibrous scar.  Triggered by the combined actions of cytokines and polypeptide growth factors CELLULAR ROLES o REPOPULATION FROM PROGENITOR CELLS.  Each cell type serves unique functions.  In situations where the proliferative 1. Epithelial cells respond to locally produced growth capacity of hepatocytes is impaired, such factors and migrate over the wound to cover it up as after chronic liver injury or 2. Endothelial cells and pericytes proliferate to form new inflammation, progenitor cells in the liver blood vessels, a process known as angiogenesis. contribute to repopulation. 3. Fibroblasts proliferate and migrate into the site of Restoration of normal tissue structure can occur only if injury and lay down collagen fibers that form the scar the residual tissue is structurally intact, as after partial 4. Macrophages play a central role in repair by clearing surgical resection offending agents and dead tissue, providing growth factors for the proliferation of various cells, and REPAIR BY CONNECTIVE TISSUE DEPOSITION secreting cytokines that stimulate fibroblast  If repair cannot be accomplished by regeneration alone, it proliferation and connective tissue synthesis and occurs by replacement of the injured cells with deposition. connective tissue, leading to the formation of a scar, or by Mostly activated (M2) type. a combination of regeneration of some residual cells formation. Angiogenesis  In contrast to regeneration, scar formation is a response  is the process of new blood vessel development from that “patches” rather than restores the tissue existing vessels. It is critical in healing at sites of injury, in the development of collateral circulations at sites of ischemia, and in allowing tumors to increase in size beyond the constraints of their original blood supply. STEPS: 1. Vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF). 2. Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout 3. Migration of endothelial cells toward the area of tissue injury. 4. Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells. 5. Remodeling into capillary tubes. STEPS IN SCAR FORMATION 6. Recruitment of periendothelial cells (pericytes for 1. Inflammation small capillaries and smooth muscle cells for larger o Breakdown produced at the site of injury function vessels) to form the mature vessel. as chemotactic agents to recruit neutrophils and 7. Suppression of endothelial proliferation and then monocytes over the next 6 to 48 hours. These migration and deposition of the basement membrane. inflammatory cells eliminate the offending agents. 2. Cell proliferation FACTORS AFFECTING ANGIOGENESIS o which takes up to 10 days, several cell types, including epithelial cells, endothelial and other  VEGF-A stimulate both migration and proliferation of vascular cells, and fibroblasts, proliferate and endothelial cells, thus initiating the process of capillary migrate to close the now clean wound. Each cell sprouting in angiogenesis. type serves unique functions.  FGF-2, stimulate the proliferation of endothelial cells, promote the migration of macrophages and fibroblasts to SAAPL | MD 2024 1  the damaged area and stimulate epithelial cell migration to pleural, peritoneal, synovial cavities) develops cover epidermal wounds. extensive exudates  Angiopoietins-structural maturation of new vessels. o Resolution-normal tissue architecture is generally  PDGF recruits smooth muscle cells. restored.  TGF-β suppresses endothelial proliferation and migration o Organization- granulation tissue grows into the and enhances the production of ECM proteins. exudate, and a fibrous scar ultimately forms.  Notch signaling pathway regulates the sprouting and branching of new vessels and thus ensures that the new HEALING OF SKIN WOUNDS vessels that are formed have the proper spacing to  Based on the nature and size of the wound, the healing of effectively supply the healing tissue with skin wounds is said to occur by first or second intention. DEPOSITION OF CONNECTIVE TISSUE HEALING BY FIRST INTENTION  The laying down of connective tissue occurs in two steps:  Injury involves only the epithelial layer. 1. Migration and proliferation of fibroblasts into the  the principal mechanism of repair is epithelial regeneration. site of injury,  Example: healing of a clean wounds 2. Deposition of ECM proteins produced by these o Wounding causes the rapid activation of cells coagulation pathways (clot) to stop bleeding and  TGF-β is the most important cytokine for the synthesis and supports migrating cells. deposition of connective tissue proteins. It is also an o Within 24 hours, neutrophils are seen at the antiinflammatory cytokine that serves to limit and terminate incision margin, migrating toward the fibrin clot. inflammatory responses. It does this by inhibiting o By day 3, neutrophils have been largely replaced lymphocyte proliferation and the activity of other leukocytes. by macrophages,  Collagen deposition is critical for the development of o By day 5, neovascularization reaches its peak as strength in a healing wound site granulation tissue fills the incisional space.  Myofibroblasts. These cells contribute to the contraction of o second week, there is continued collagen the scar over time. accumulation and fibroblast proliferation. o end of the first month, the scar comprises a cellular FACTORS THAT INFLUENCE TISSUE REPAIR connective tissue largely devoid of inflammatory 1. Infection is clinically one of the most important causes cells and covered by an essentially normal of delayed healing; it prolongs inflammation and epidermis. potentially increases the local tissue injury. 2. Diabetes is a metabolic disease that compromises tissue repair for many reasons and is one of the most important systemic causes of abnormal wound healing. 3. Nutritional status has profound effects on repair; protein deficiency and vitamin C deficiency inhibit collagen synthesis and retard healing. 4. Glucocorticoids (steroids) have well-documented antiinflammatory effects, and their administration may result in weakness of the scar due to inhibition of TGF- β production and diminished fibrosis 5. Mechanical factors such as increased local pressure or torsion may cause wounds to pull apart 6. Poor perfusion, due to peripheral vascular disease, arteriosclerosis, and diabetes or due to obstructed venous drainage (e.g., in varicose veins), also impairs healing. HEALING BY SECOND INTENTION 7. Foreign bodies such as fragments of steel, glass, or  also called secondary union. even bone impede healing by perpetuating chronic  large tissue deficits, the fibrin clot is larger, and there is inflammation. more exudate and necrotic debris 8. The type and extent of tissue injury and the  larger amounts of granulation tissue. character of the tissue in which the injury occurs affect the subsequent repair. Complete restoration can  By the end of the first month, the scar is made up of acellular occur only in tissues composed of stable and labile connective tissue devoid of inflammatory infiltrate. cells. Injury to tissues composed of permanent cells  Wound contraction helps to close the wound by inevitably results in scarring and some loss of function. myofibroblast 9. The location of the injury is also important. For  within 6 weeks, large skin defects may be reduced to 5% to example, inflammation arising in tissue spaces (e.g., 10% of their original size, largely by contraction. SAAPL | MD 2024 1   The lesions are caused by mechanical pressure and local ischemia EXCESSIVE SCARRING  Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids  Hypertrophic Scar o raised scar accumulation of excessive amounts of collagen. o grow rapidly and contain abundant myofibroblasts, but they tend to regress over several months. o Hypertrophic scars generally develop after thermal or traumatic injury that involves the deep layers of the dermis  Keloid o scar tissue grows beyond the boundaries of the WOUND STRENGTH original wound and does not regress.  Carefully sutured wounds have approximately 70% of the o Keloid formation seems to be an individual strength of normal skin, largely because of the placement predisposition, and for unknown reasons it is of sutures. somewhat more common in African Americans  The recovery of tensile strength results from the excess of collagen synthesis over collagen degradation during the LEGEND first 2 months of healing by cross-linking of collagen fibers  📖: From the book and increased fiber size.  🔎: From the internet  Wound strength reaches approximately 70% to 80% of  Sample text: From instructor’s discussion normal by 3 months but usually does not substantially improve beyond that point. FIBROSIS IN PARENCHYMAL ORGANS  Fibrosis used to denote the excessive deposition of collagen and other ECM components in a tissue.  Fibrotic disorders include diverse chronic and debilitating diseases such as liver cirrhosis, systemic sclerosis (scleroderma), fibrosing diseases of the lung DEFECTS IN HEALING: CHRONIC WOUNDS 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.  These lesions can be quite painful and reddish DIABETIC ULCERS  Affect the lower extremities, particularly the feet.  There is tissue necrosis and failure to heal as a result of vascular 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 PRESSURE SORES  areas of skin ulceration and necrosis of underlying tissues caused by prolonged compression of tissues against a bone, e.g., in elderly patients with numerous morbidities lying in bed without moving. SAAPL | MD 2024 1