Pathophysiology lec.3.pdf

3th year Pathophysiology lecture 3 1st semester Inflammation and tissue repair Lect. Ehab Hamed Abdul-Mageed AL-Kunooze University-College of Pharmacy Definition of Inflammation Inflammation is the reaction of vascularized tissues to cell injury or death...

3th year Pathophysiology lecture 3 1st semester Inflammation and tissue repair Lect. Ehab Hamed Abdul-Mageed AL-Kunooze University-College of Pharmacy Definition of Inflammation Inflammation is the reaction of vascularized tissues to cell injury or death. It is characterized by the production and release of inflammatory mediators and the movement of fluid and leukocytes from the vasculature into the extravascular tissues. Inflammation is a complex nonspecific response to tissue injury intended to minimize the effects of injury or infection, remove the damaged tissue, generate new tissue and facilitate healing. Inflammation can be acute or chronic. What the purpose of acute inflammation? Causes of inflammation 1.Infections (bacteria, virus, fungus, parasite) and microbial toxins are among the most common causes of inflammation. 2.Physical agents and chemical agents: like thermal injury, as in burns or frostbite, radiation, mechanical trauma and caustic chemicals. 3.Immune reactions: include autoimmune diseases and hypersensitivity. 4.Foreign bodies: may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes. 5.Tissue necrosis from any cause Name of inflammatory disease Inflammatory conditions are commonly named by adding the suffix –it is to the affected organ or system, for example: Appendicitis refers to inflammation of the appendix. pericarditis refers to inflammation of the pericardium. Neuritis refers to inflammation of a nerve. Meningitis refers to inflammation of the meninges. Glossitis refers to inflammation of the tongue. Gastritis is inflammation of the lining of the stomach. Nephritis is inflammation of the kidneys. Signs of inflammation Signs of inflammation can be local and/or systemic 1-Cardinal signs or Local signs of inflammation include: 1- Heat 2- Redness 3- Swelling 4- Pain 5- Loss of function 2-Systemic manifestations such as fever and it is caused by a cytokine change in the set point of the hypothalamic thermoregulatory center and Leukocytosis, or the increase in white blood cells. Usually, in bacterial infections there is neutrophilia; in viral infections lymphocytosis; and in parasitic infestations, eosinophilia. Types of inflammation Depending upon the defense capacity of the host and duration of response, inflammation can be classified as: 1. Acute inflammation: it is the initial, rapid response to infections and tissue damage. It is short duration, lasting from a few minutes to several days. Its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, mainly neutrophils (also called poly morphonuclear neutrophils (PMNs)). 2. Chronic inflammation: It is longer duration, lasting for weeks, months or even years. Its main characteristics are more tissue destruction, the presence of lymphocytes and macrophages, the proliferation of blood vessels and fibrosis. Acute inflammation vs Chronic inflammation Acute inflammation vs Chronic inflammation Acute inflammation vs Chronic inflammation Inflammatory cells of acute and chronic inflammation. A) Acute inflammation with densely packed poly morphonuclear neutrophils with multi-lobed nucleus (arrows). B) Chronic inflammation with lymphocytes, plasma cells (arrows) and a few macrophages. Cells involved in the inflammatory process Many cells and tissue components are involved in the inflammatory process, including: 1- The endothelial cells: that line blood vessels. 2- The platelets. 3- The leukocytes: neutrophils in acute inflammation and macrophages, lymphocytes and plasma cells, eosinophils, and mast cells in chronic inflammation. 4- The connective tissue cells: including mast cells, fibroblasts, tissue macrophages, and components of the extracellular matrix. Acute inflammation Acute inflammation is the immediate and early response to an injurious agent. The response, which serves to control and eliminate altered cells, microorganisms and antigens, occurs in two phases: 1. Vascular phase: alteration in the microvasculature (arterioles, capillaries and venules) is the earliest response to tissue injury. These alterations include: blood flow changes and changes in vascular permeability (vasodilation). 2. Cellular phase: The cellular phase of inflammation consists of two processes: Leukocyte recruitment and phagocytosis and their accumulation at the site of injury or infection. Vascular phase The vascular changes begin almost immediately after injury and the sequence of these changes is: 1.Transient vasoconstriction of arterioles lasting a few seconds in order to reduce blood loss and form clot to stop the bleeding. 2. Vasodilatation resulting in increased blood volume therefore, the area becomes congested, causing redness (erythema) and warmth at the site of acute inflammation. Vasodilation is induced by the action of several mediators, mostly histamine. 3. Increased vascular permeability it is characterized by leakage of a protein rich fluid (exudate) into the extravascular spaces. vascular permeability induced by binding of the chemical mediators (such as histamine, bradykinin, leukotrienes) to endothelial receptors causes contraction of endothelial cells and separation of intercellular junctions. The loss of fluid results in an increased concentration of blood constituents (red blood cells, leukocytes, platelets, and clotting factors), stagnation of flow, and clotting of blood at the site of injury. This aids in localizing the spread of infectious microorganisms. Cellular phases The cellular phase of inflammation consists of two processes: A. Leukocyte Recruitment to the sites of Inflammation: This process can be divided into: 1. Margination: The normal axial flow consists of 1) the central stream of cells comprised of leucocytes and RBCs and 2) the peripheral cell-free layer of plasma close to vessel wall. Due to slowing and stasis, the neutrophils of the central column come close to the vessel wall. 2. Rolling and adhesion: Peripherally emarginated neutrophils slowly roll over the endothelial and adhere tightly to the endothelial cells. Rolling and adhesion phases are mediated by several molecules such as selectins and integrin's. 3. Transmigration: the neutrophils throw out cytoplasmic pseudopods in a suitable site between the endothelial cells. Subsequently, the neutrophils lodged between the endothelial cells and cross the basement membrane by damaging it locally with secreted collagenases and escape out into the extravascular space. 4. Chemotaxis: the directed movement of leukocytes to the site of infection, it is guided by chemo-attractants such as chemokines, bacterial and macrophages. Cellular phases B. Phagocytosis is defined as the process of engulfment of solid particulate material by the cells (cell-eating). The cells performing this function are called phagocytes. There are two main types of phagocytic cells: 1- Poly morphonuclear neutrophils (PMNs) which are the main cells in acute inflammation in the first 24 hours, sometimes called as microphages. Neutrophils are short-lived (24-48 hours) 2- Monocyte-macrophages appear in the next 24-48 hours, monocyte-macrophages survive much longer. The microbe undergoes the process of phagocytosis by polymorphs and macrophages and involves the following 3 steps 1. Recognition and attachment: recognition and binding of particles by specific receptors on the surface of phagocytic cells. 2. Engulfment: extensions of cytoplasm move around and eventually enclose the particle in a membrane-surrounded phagocytic vesicle or phagosome. 3. Killing and degradation: the phagosome merges with a cytoplasmic lysosome containing antibacterial molecules and enzymes that can kill and digest the microbe. Types of acute inflammation Acute inflammation response involves the production of exudates, these exudates vary in terms of fluid type and they can be: 1) Serous exudate: they are watery fluids low in protein content that result from plasma entering the inflammatory site. 2) Hemorrhagic exudate: they occur when there is severe tissue injury that causes damage to blood vessels or when there is significant leakage of red cells from the capillaries. 3) Fibrinous exudate: they contain large amounts of fibrinogen and form a thick and sticky meshwork, much like the fibers of a blood clot. 4) Membranous or pseudomembranous exudate: when the surface inflammation of epithelium produces increased secretion of mucous e.g. common cold. 5) Supportive (purulent) exudate: it contains pus, which is composed of degraded white blood cells, proteins, and tissue debris. Fate of acute inflammation Acute inflammatory reactions typically have one of the following outcomes:- 1. Complete resolution: It means complete return to normal tissue following acute inflammation. 2. Scarring and fibrosis: Healing by fibrosis occurs when the tissue destruction in acute inflammation is extensive or when inflammation occurs in tissues that do not regenerate takes place. 3. Progression to chronic inflammation: acute inflammation may progress to chronic inflammation if the offending agent is not removed. Chronic inflammation Definition of chronic inflammation is a response of prolonged duration lasting for weeks, months or even years. chronic inflammation is characterized by the following: 1- Infiltration of macrophages, lymphocytes and plasma cells (angiogenesis). 2- Tissue destruction (necrosis). 3- Tissue repair (scarring). Causes of chronic inflammation 1. Start as chronic inflammation: A- Infection with microorganisms that are difficult to kill, such as Mycobacterium tuberculosis and certain viruses, fungi, and parasites. B- Prolonged exposure to exogenous or endogenous toxic agents: silica is an example of an exogenous agent that causes an inflammatory lung disease called silicosis. Atherosclerosis is a chronic inflammatory process affecting the arterial wall that is thought to be induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids. 2. Chronic inflammation following acute inflammation: due to recurrent attacks of acute inflammation. e.g. in recurrent urinary tract infection leading to chronic pyelonephritis, repeated acute infection of gallbladder leading to chronic cholecystitis. 3. Immune and hypersensitivity diseases: Under certain conditions, immune reactions may develop against the person’s own tissues, leading to autoimmune disease such as rheumatoid arthritis and multiple sclerosis Cancers associated with chronic infection and inflammation The recurrent and persistent inflammation may induce, promote or influence susceptibility to cancer by: 1- causing DNA damage. 2- inciting tissue reparative proliferation, and/or creating an environment that is enriched with cytokines and growth factors that favour tumor development and growth. Examples: 1. human papillomavirus (HPV) causes cervical cancer. 2. hepatitis B and C cause cancer of the liver. 3. Helicobacter pylori causes cancer of the stomach. 4. chronic cholecystitis and cholelithiasis cause cancer of the gallbladder Granulomatous inflammation Granulomatous inflammation: is a special type of chronic inflammation, typically itis a small lesion (1- to 2 mm) consisting of a collection of activated macrophages surrounded by lymphocytes and sometimes associated with central necrosis. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells. Some activated macrophages may fuse, forming multinucleate giant cells. Granulomatous inflammation Causes of granulomatous inflammation Granuloma formation is a cellular attempt to contain type of agent that is difficult to eradicate. Types of agent that are difficult to eradicate include: 1. Foreign bodies such as splinters and silica. 2. Microorganisms such as that cause tuberculosis and syphilis. Granulomatous inflammation Cell proliferation and tissue regeneration and repair Tissue regeneration Tissue regeneration refers to the restoration of injured tissue to its normal structure and function by cell proliferation. Cell proliferation refers to the process of increasing cell numbers by cell division. This process is regulated by the multiple phases of the cell cycle. The cell cycle is the regular sequence of events that produce new cells Cell cycle The cell cycle has two major phases: 1. Interphase: a longer period of time during which the cell increases its size and content and replicates its genetic material. The interphase is subdivided into three phases 1- G1 (gap 1) phase: A cell doubles its organelles (e.g., mitochondria and ribosomes), and it accumulates the materials needed for DNA synthesis. 2- S (synthetic) phase: DNA replication occurs. 3- G2 (the gap between DNA duplication and the next mitosis). The cell synthesizes the proteins needed for cell division, such as the protein found in microtubules. 2. Mitosis: the short period of time during which the cell divides its nucleus and cytoplasm, giving rise to two daughter cells. cells may exit the cell cycle and reside in a special resting state known as G0 Cell Cycle Control The cell cycle is controlled by: Checkpoints Each step of the cell cycle is monitored by internal controls called checkpoints. which can delay the cell cycle until certain conditions are met. The three major checkpoints in the cell cycle are: G1/S checkpoint: start or restriction checkpoint just before the start of S. G2/M checkpoint: that ensures that DNA Replication is complete. M checkpoint: here, the cell examines whether all the sister chromatids are correctly attached to the spindle microtubules. Failure of the cell cycle control mechanisms may result in unrestricted cell growth, or cancer. Are all our cell types entering the cell cycle? There are three main types of cells in the body depending upon their regenerative capacity: 1- The labile cells: are under continuous active division and replace the cells that are lost from the body. Examples of labile cells include epidermis cell and hematopoietic stem cell. 2- The stable cells: have a long life span and divide at a very slow rate such as liver. They are capable of undergoing rapid division upon injury to the organ to replace the dead cells. Regeneration following injury in the tissues that contain stable cells requires having at least some healthy cells remaining to undergo proliferation and regeneration. 3- Permanent cells: do not divide in postnatal life such as the neuron and cardiac and skeletal muscles. Due to the inability in proliferation, injury to such tissue results in a scar formation and a permanent loss of function Healing by connective tissue repair When regeneration cannot occur, healing by replacement with a connective (fibrous) tissue occurs, a process that terminates in scar formation. Phases of repair Repair by connective tissue deposition can be divided into three phases: 1- Angiogenesis is induced by several growth factors but the most important is vascular endothelial growth factor (VEGF) which stimulates both proliferation and motility of endothelial cells, thus initiating the process of new blood vessels. 2- Emigration of fibroblasts and deposition of extracellular matrix. 3- Maturation and reorganization of the fibrous tissue (remodeling) References - Robbins Basic Pathology 9th edition. - Carol Mattson Porth - Essentials of Pathophysiology 4rd edition.