Inflammation chapter 3 Flashcards
What is the first step in the inflammatory response?
Recognition of the noxious agent that initiates inflammation.
Why must inflammation be regulated?
To prevent excessive tissue damage and terminate the response once the threat is eliminated.
What happens after immune cells recognize the noxious agent?
They release inflammatory mediators, triggering the inflammatory response
What is the second step of inflammation?
Recruitment of leukocytes and plasma proteins from blood to the injury site.
What enables immune cells and proteins to exit blood vessels?
Blood vessel changes and secretion of inflammatory mediators.
Which immune cells arrive first and later?
Neutrophils arrive first, followed by monocytes and lymphocytes.
What is the third step of inflammation?
Removal of the noxious agent by phagocytic cells (ingestion and destruction of microbes & dead cells).
What is the final step of inflammation?
Tissue repair via cell regeneration or scarring (connective tissue replacement).
What are the major components of the inflammatory response?
Blood vessels and leukocytes. Blood vessels dilate and increase permeability to allow proteins and immune cells into tissues. The endothelium changes to help leukocytes adhere and migrate into tissues. Once recruited, leukocytes ingest and destroy microbes, dead cells, and foreign materials.
What are the harmful consequences of inflammation?
Inflammation can cause local tissue damage, leading to pain and functional impairment. Normally, this damage is self-limited. However, in diseases like autoimmune disorders (e.g., rheumatoid arthritis), allergies, and chronic inflammatory diseases (e.g., atherosclerosis, lung fibrosis), inflammation becomes the primary cause of tissue damage. Uncontrolled inflammation is linked to conditions like type 2 diabetes, Alzheimerβs disease, and cancer.
What is the difference between acute and chronic inflammation?
Acute inflammation: Rapid and short-lived, mainly involving neutrophils, fluid exudation, and plasma proteins. It subsides if the stimulus is eliminated, with minimal residual damage.
Chronic inflammation: Long-term, involves lymphocytes and macrophages, and leads to more tissue destruction and fibrosis. It can arise de novo or follow unresolved acute inflammation (e.g., peptic ulcers). It occurs in persistent infections (e.g., tuberculosis), autoimmune diseases, and long-term exposure to irritants.
How does local inflammation differ from systemic inflammation?
Local inflammation occurs at a specific site of infection or injury and may cause fever. It develops within minutes to hours, lasts a few days, and is marked by fluid exudation (edema) and neutrophil infiltration. Systemic inflammation, such as sepsis, involves widespread pathological abnormalities due to bacterial infections and is part of the systemic inflammatory response syndrome (SIRS).
What are the mediators of inflammation, and how do they function?
nflammatory mediators are soluble factors produced by cells or derived from plasma proteins. They are triggered by microbes, necrotic cells, or hypoxia and determine the pattern, severity, and manifestations of inflammation.
How does the immune system recognize inflammatory triggers?
Cellular receptors for microbes β Found on plasma membranes, endosomes, and cytosol, detecting microbes in different cellular compartments.
Toll-like receptors (TLRs) are key in sensing pathogens and activating inflammation.
Found in epithelial cells, dendritic cells, macrophages, and leukocytes.
Sensors of cell damage β NOD-like receptors (NLRs) detect uric acid, ATP, K+ loss, and misplaced DNA, activating the inflammasome, which produces IL-1, leading to leukocyte recruitment and inflammation.
IL-1 overproduction can cause autoinflammatory syndromes (e.g., gout, metabolic syndrome, Alzheimerβs).
Other receptors β Leukocytes have receptors for Fc tails of antibodies and complement proteins, recognizing opsonized microbes for enhanced immune response.
What are the major causes of inflammation?
Infections β Bacterial, viral, fungal, and parasitic infections trigger varied inflammatory responses. Some resolve quickly, while others cause chronic damage or systemic reactions (e.g., sepsis).
Tissue necrosis β Inflammation occurs regardless of the cause of cell death (e.g., ischemia, trauma, burns, frostbite, chemical injury). Necrotic cells release molecules that trigger inflammation.
Foreign bodies β Splinters, dirt, and sutures induce inflammation directly or by causing trauma or introducing microbes. Even endogenous substances like urate crystals (gout), cholesterol crystals (atherosclerosis), and lipids (metabolic syndrome) can trigger inflammation.
Immune reactions (hypersensitivity) β Autoimmune diseases, allergies, and inappropriate immune responses lead to persistent inflammation due to self-antigens or environmental antigens, driven mainly by cytokines from T lymphocytes.
What are the three major components of acute inflammation?
Vasodilation β Small vessels dilate, increasing blood flow.
Increased vascular permeability β Plasma proteins and leukocytes leave circulation.
Leukocyte recruitment and activation β Leukocytes emigrate to the injury site, accumulate, and eliminate the offending agent.
Triggering event: Phagocytes recognize microbes or dead cells β release cytokines & lipid mediators β initiate vascular changes and leukocyte recruitment.
What circulating proteins contribute to inflammation?
Complement system β Reacts against microbes and produces inflammatory mediators.
Mannose-binding lectin β Recognizes microbial sugars, promoting complement activation and phagocytosis.
Collectins β Bind and combat microbes, aiding in immune defense.
What are the key vascular reactions in acute inflammation?
Exudation β Movement of fluid, proteins, and blood cells into tissues.
Exudate: High-protein, contains cellular debris β indicates inflammation.
Transudate: Low-protein, few cells β caused by osmotic/hydrostatic imbalance.
Edema: Excess fluid in tissues (can be either exudate or transudate).
Pus (Purulent Exudate): Rich in neutrophils, dead cells, and microbes.
What are the changes in vascular flow and caliber during acute inflammation?
Vasodilation β Mediated by histamine, affecting arterioles and capillary beds β causes heat and redness (erythema).
Increased vascular permeability β Leads to leakage of protein-rich fluid into tissues (discussed in detail later).
Stasis formation β Loss of fluid + vessel dilation = slower blood flow, increased viscosity, and vascular congestion (causing localized redness).
Leukocyte recruitment β
Neutrophils accumulate along vessel walls.
Endothelial cells upregulate adhesion molecules, allowing leukocytes to adhere and migrate into tissues.
What is the most common mechanism of vascular permeability in acute inflammation, and how does it occur?
Endothelial cell contraction leads to interendothelial gaps in postcapillary venules.
Mediated by: Histamine, bradykinin, leukotrienes, etc.
Two types:
Immediate transient response (15β30 min, short-lived).
Delayed prolonged response (2β12 hrs, lasts days; seen in burns, UV exposure, toxins).
What secondary inflammatory conditions can develop in the lymphatic system during acute inflammation?
Lymphangitis: Inflammation of lymphatic vessels (red streaks near wounds suggest infection).
Lymphadenitis: Inflammation of draining lymph nodes due to hyperplasia of immune cells.
Reactive (inflammatory) lymphadenitis: Lymph node swelling due to immune activation.
How do lymphatic vessels respond to acute inflammation?
Increased drainage of edema fluid, leukocytes, debris, and microbes.
Lymphatic vessel proliferation to accommodate excess fluid.
Prevents excessive tissue swelling and helps in immune surveillance.
How does direct endothelial injury contribute to increased vascular permeability?
Occurs in severe burns, bacterial toxins, or neutrophil-mediated injury.
Endothelial necrosis & detachment β immediate & sustained leakage until vessel repair or thrombosis.
Leukocyte-dependent injury amplifies inflammation by damaging endothelial cells.
What are key clinical signs indicating lymphatic system involvement in inflammation?
Red streaks near a wound β Lymphangitis (infection spreading through lymphatics).
Painful swollen lymph nodes β Lymphadenitis (immune activation).
Systemic symptoms (fever, malaise) may indicate significant lymphatic involvement.
What is the role of leukocytes in acute inflammation?
Leukocytes (primarily neutrophils and macrophages) are essential for eliminating pathogens, necrotic tissue, and foreign substances.
Macrophages also promote tissue repair through growth factor production.
Leukocytes are key for inflammation, but their activation can result in tissue damage and prolonged inflammation due to the release of destructive substances.
What are the three major phases of leukocyte migration in inflammation?
Margination, Rolling, and Adhesion:
As blood flow slows, leukocytes move to the vessel wall (margination), roll along it (rolling), and adhere firmly via adhesion molecules (selectins, integrins).
Migration through Endothelium:
Leukocytes cross the endothelial layer into the tissue, a process called transmigration or diapedesis.
Chemotaxis:
Leukocytes follow a chemotactic gradient created by cytokines (chemokines) and other attractants to reach the site of injury or infection.
How do leukocytes adhere to the endothelium during inflammation?
Margination occurs when leukocytes move toward the endothelium as blood flow slows.
Rolling happens when leukocytes interact with selectins on the endothelial surface.
Firm adhesion occurs through integrins, such as LFA-1 and VLA-4, which bind to endothelial VCAM-1 and ICAM-1.
What roles do selectins and integrins play in leukocyte adhesion?
Selectins mediate weak, transient interactions for rolling:
L-selectin (on leukocytes), E-selectin (on endothelium), and P-selectin (on platelets and endothelium).
Integrins mediate strong adhesion to endothelium:
Integrins like LFA-1 and VLA-4 bind to ligands like VCAM-1 and ICAM-1 on endothelial cells.
Cytokines (TNF, IL-1) and other mediators (e.g., histamine, thrombin) enhance selectin and integrin expression.
How do chemokines influence leukocyte recruitment?
Chemokines create a chemical gradient at the site of injury or infection, guiding leukocytes toward the affected area.
They bind to leukocyte receptors, triggering activation of integrins like LFA-1 and VLA-4, enhancing leukocyte adhesion to the endothelial surface.
This ensures leukocytes are directed to the site of infection, where they help eliminate pathogens and damaged cells.
Leukocyte Migration through Endothelium
After adhering to the endothelium, leukocytes transmigrate (pass through) by interacting with PECAM-1 and other adhesion molecules.
Leukocytes secrete collagenases to break through the basement membrane and enter the tissue.
They follow a chemotactic gradient formed by cytokines and other signals, accumulating at the site of injury or infection.
What happens in the absence of functional leukocyte adhesion molecules?
Leukocyte adhesion deficiencies (LAD) result in impaired leukocyte adhesion to endothelial cells, leading to a failure of leukocytes to migrate to infection sites.
This makes individuals with LAD more susceptible to bacterial infections, as the immune response is hindered.
How do cytokines regulate the process of leukocyte recruitment?
Cytokines like TNF and IL-1 are released in response to infection or injury.
These cytokines activate the endothelium to express selectins and integrin ligands, promoting leukocyte rolling and firm adhesion to the vessel wall.
They also stimulate chemokine production, which guides leukocytes to the site of injury or infection.
What is chemotaxis, and what is its role in inflammation?
Chemotaxis is the movement of leukocytes toward the site of injury along a chemical gradient. It plays a crucial role in directing immune cells to the site of infection or injury.
How does the interaction between leukocytes and endothelial cells progress during inflammation?
Leukocytes initially roll on endothelial cells due to weak selectin-mediated interactions.
Firm adhesion follows when integrins on leukocytes bind to endothelial VCAM-1 and ICAM-1, triggered by chemokine activation.
After adhesion, leukocytes undergo transmigration (diapedesis), passing through endothelial gaps and entering the tissue to fight infection or aid in tissue repair.
What are the major exogenous and endogenous chemoattractants involved in chemotaxis?
Exogenous chemoattractants: Bacterial products, such as peptides with N-formylmethionine and some lipids.
Endogenous chemoattractants:
Cytokines, especially chemokines like IL-8.
Complement system components, notably C5a.
Arachidonic acid metabolites, such as leukotriene B4 (LTB4).
How do leukocytes move toward the site of injury during chemotaxis?
Leukocytes move by reorganization of their cytoskeleton. Signals from chemotactic agents activate receptors on leukocytes, leading to actin polymerization at the leading edge, allowing the cell to extend filopodia and move in the direction of the chemoattractant.
What is the pattern of leukocyte infiltration in acute inflammation?
First 6-24 hours: Neutrophils predominate.
24-48 hours: Neutrophils are replaced by monocytes.
Monocytes survive longer and may proliferate in tissues, becoming the dominant cell type in prolonged inflammation.
How does leukocyte infiltration vary in different types of infections?
Pseudomonas infections: Continuous recruitment of neutrophils.
Viral infections: Lymphocytes may be the first cells to arrive.
Hypersensitivity reactions: Dominated by lymphocytes, macrophages, and plasma cells.
Helminthic and allergic reactions: Eosinophils may dominate.
What are the two major phagocytes, and how do they differ?
The two major phagocytes are neutrophils and macrophages.
Neutrophils: Short-lived, first responders in acute inflammation, rapid response.
Macrophages: Longer-lived, can proliferate in tissues, dominate in chronic inflammation, also involved in tissue repair.
What triggers leukocyte activation, and what are its key intracellular effects?
Leukocyte activation is triggered by microbe or dead cell recognition, leading to:
Increased cytosolic CaΒ²βΊ levels.
Activation of protein kinase C and phospholipase Aβ.
Key functional responses: phagocytosis and intracellular killing.
What are the three key steps of phagocytosis?
Recognition and attachment of the target to the phagocyte.
Engulfment and formation of a phagocytic vacuole.
Intracellular killing and degradation of ingested material.
What are the major receptors involved in phagocytosis?
Mannose receptor: Recognizes microbial mannose and fucose residues.
Scavenger receptors: Bind oxidized LDL and microbes.
MAC-1 (CD11b/CD18): Macrophage integrin that binds microbes.
Opsonin receptors (enhance phagocytosis):
IgG antibodies
C3b (complement fragment)
Mannose-binding lectin (MBL) and collectins
What are the main intracellular killing mechanisms used by phagocytes?
Reactive oxygen species (ROS) β oxidative burst produces free radicals.
Reactive nitrogen species (NO) β derived from nitric oxide.
Lysosomal enzymes β degrade microbial components.
How do phagocytes prevent self-damage during microbial killing?
Toxic molecules (ROS, NO, enzymes) are contained within lysosomes.
Phagocytosed material is segregated from the cellβs cytoplasm and nucleus to prevent damage to the phagocyte.
How are reactive oxygen species (ROS) produced in phagocytes?
ROS are generated by NADPH oxidase (phagocyte oxidase), which:
Converts oxygen into superoxide anion (Oβ*).
Superoxide anion is converted into hydrogen peroxide (HβOβ).
HβOβ alone is weak but becomes highly microbicidal when converted by myeloperoxidase (MPO).
What is the respiratory burst in neutrophils?
A rapid increase in oxygen consumption during phagocytosis, activating NADPH oxidase, which produces ROS.
Phagocyte oxidase is a seven-protein enzyme complex that assembles on the phagolysosome membrane after activation.
ROS production occurs inside the phagolysosome to kill microbes while protecting the host cell.
What is the most potent bactericidal system in neutrophils?
The HβOβ-MPO-halide system, which:
Uses myeloperoxidase (MPO) to convert HβOβ and Clβ» into hypochlorite (HOCl*) (active in household bleach).
Destroys microbes by halogenation (binding halides to microbial molecules) and oxidation.
Besides HOCl*, what other ROS contribute to microbial killing?
Hydroxyl radical (*OH) β highly destructive to proteins, lipids, and DNA.
Superoxide anion (Oβ*) β precursor to other ROS.
How do ROS contribute to inflammation-associated tissue damage?
ROS can leak from phagocytes and damage host tissues.
Triggered by microbes, chemokines, antigen-antibody complexes, or phagocytic stimuli.
Cause oxidative damage to lipids, proteins, and nucleic acids.
How does the body protect itself from ROS?
Antioxidants neutralize harmful oxygen radicals:
Superoxide dismutase (SOD) β Converts superoxide (Oβ*) into HβOβ.
Catalase β Detoxifies HβOβ into water and oxygen.
Glutathione peroxidase β Detoxifies HβOβ using glutathione.
Ceruloplasmin (copper-containing plasma protein).
Transferrin (iron-free fraction of plasma).
What is chronic granulomatous disease (CGD)?
An inherited immunodeficiency caused by defective phagocyte oxidase (NADPH oxidase), leading to:
Impaired ROS production and defective microbial killing.
Chronic infections and granuloma formation.
How does nitric oxide (NO) contribute to microbial killing?
NO is produced by inducible nitric oxide synthase (iNOS) in activated macrophages.
Reacts with superoxide (Oβ*) to form peroxynitrite (ONOOβ»), a highly reactive free radical.
Damages microbial lipids, proteins, and DNA, similar to ROS.
What are the three types of NOS and their functions?
eNOS (endothelial NOS) β Maintains vascular tone.
nNOS (neuronal NOS) β Acts as a neurotransmitter.
iNOS (inducible NOS) β Microbicidal; induced by IFN-Ξ³ and microbial products in macrophages.
What is the vascular function of NO in inflammation?
NO promotes vasodilation by relaxing vascular smooth muscle
Why does MPO deficiency cause only a mild increase in infection risk?
Multiple overlapping microbicidal mechanisms exist, including:
ROS (other than MPO-HβOβ-halide system).
Nitric oxide and peroxynitrite (NO-derived radicals).
Lysosomal enzymes.
What are the two main types of neutrophil granules, and what do they contain?
Specific (secondary) granules β Contain lysozyme, collagenase, gelatinase, lactoferrin, plasminogen activator, histaminase, and alkaline phosphatase.
Azurophil (primary) granules β Contain myeloperoxidase (MPO), bactericidal proteins (lysozyme, defensins), acid hydrolases, and neutral proteases (elastase, cathepsin G, proteinase 3, nonspecific collagenases).
What are the functions of lysosomal enzymes in phagocytes?
Acid proteases β Degrade bacteria and debris inside phagolysosomes (require acidic pH).
Neutral proteases β Degrade extracellular components (collagen, basement membrane, fibrin, elastin, cartilage), promoting tissue destruction.
Neutral proteases also activate inflammatory mediators:
Cleave C3 and C5 complement proteins β inflammation.
Release kinin-like peptides from kininogen.
Neutrophil elastase β Degrades bacterial virulence factors, aiding in infection control.
Macrophages also contain acid hydrolases, collagenase, elastase, phospholipase, and plasminogen activator.
How are harmful lysosomal enzymes controlled to prevent tissue damage?
Ξ±1-Antitrypsin β Major inhibitor of neutrophil elastase. Deficiency leads to emphysema due to lung tissue destruction.
Ξ±2-Macroglobulin β Another antiprotease in serum and secretions.
These antiproteases prevent excessive tissue damage caused by leukocyte proteases.
What are other microbicidal substances found in neutrophil granules?
Defensins β Cationic, arginine-rich peptides toxic to microbes.
Cathelicidins β Antimicrobial proteins found in neutrophils and other cells.
Lysozyme β Hydrolyzes the muramic acid-N-acetylglucosamine bond in bacterial cell walls.
Lactoferrin β Iron-binding protein in specific granules that limits bacterial growth.
Major Basic Protein (MBP) β Found in eosinophils, cytotoxic to helminths but has limited bactericidal activity
What are NETs, and how do they function?
NETs are extracellular fibrillar networks of nuclear chromatin that trap microbes and concentrate antimicrobial substances at infection sites.
Produced by neutrophils in response to bacteria, fungi, chemokines, cytokines (mainly interferons), complement proteins, and ROS.
Contain granule proteins such as antimicrobial peptides and enzymes.
Prevent microbial spread but can expose nuclear antigens, contributing to autoimmune diseases (e.g., lupus).
How are NETs formed?
ROS-dependent activation of arginine deaminase β converts arginines to citrulline β chromatin decondensation.
MPO and elastase enter the nucleus β further chromatin decondensation.
Nuclear envelope ruptures β chromatin is released as NETs.
Neutrophil loses its nucleus and dies.
NETs have been detected in sepsis and may contribute to autoimmune diseases by exposing nuclear material.
In what situations do leukocytes cause tissue damage?
Collateral damage during infection β Some infections (e.g., tuberculosis, viral infections) cause prolonged immune responses that damage host tissues.
Autoimmune diseases β The immune system attacks self-tissues inappropriately.
Allergic reactions β The immune system overreacts to harmless substances (e.g., asthma).
What is βfrustrated phagocytosis,β and how does it lead to tissue injury?
Occurs when phagocytes encounter materials too large to ingest (e.g., immune complexes on glomerular basement membrane).
Triggers strong activation and release of lysosomal enzymes into the extracellular environment.
Certain phagocytosed substances (e.g., urate crystals) can damage phagolysosome membranes, causing enzyme leakage and tissue damage.
Besides microbial killing, what other roles do activated leukocytes play?
Macrophages secrete:
Cytokines β Regulate inflammation (amplify or limit).
Growth factors β Stimulate endothelial & fibroblast proliferation, collagen synthesis.
Enzymes β Remodel connective tissue.
Macrophages are key players in chronic inflammation and tissue repair.
How do T lymphocytes contribute to acute inflammation?
Th17 cells produce IL-17, which induces chemokine secretion to recruit more leukocytes.
Th17 deficiency leads to:
Increased fungal and bacterial infections.
βCold abscessesβ β Skin abscesses lacking typical inflammation signs (redness, warmth).
What mechanisms help terminate acute inflammation?
Short-lived mediators β Inflammatory mediators degrade quickly after the stimulus is gone.
Neutrophil apoptosis β Neutrophils die by apoptosis within hours after leaving the blood.
Switch to anti-inflammatory mediators:
Leukotrienes β Lipoxins (anti-inflammatory arachidonic acid metabolites).
Anti-inflammatory cytokines:
TGF-Ξ² (Transforming Growth Factor-Ξ²)
IL-10 (produced by macrophages).
Neural regulation β Cholinergic (vagus nerve) signals inhibit TNF production in macrophages.
What are the most important mediators of acute inflammation?
Vasoactive amines (e.g., histamine, serotonin)
β
Lipid products (e.g., prostaglandins, leukotrienes)
β
Cytokines (e.g., TNF, IL-1, chemokines)
β
Complement system proteins
How are mediators produced?
Cell-derived mediators: Stored in granules (e.g., histamine in mast cells) or synthesized de novo (e.g., prostaglandins, leukotrienes, cytokines).
Plasma-derived mediators: Produced by the liver, circulate as inactive precursors, and require proteolytic activation (e.g., complement proteins).
Key Features of Inflammatory Mediators:
βActivated only when needed β Triggered by microbial products or necrotic cell debris.
β Short-lived β Quickly degraded or inactivated to prevent excessive inflammation.
β Regulated by checks and balances β Prevents excessive tissue damage.
β Can trigger cascades β One mediator can stimulate the release of others (e.g., complement proteins stimulate histamine release, TNF stimulates IL-1 production).
What are vasoactive amines?
Histamine & Serotonin β First mediators released in acute inflammation, stored as preformed molecules in cells.
Main Sources of Histamine
Mast cells (richest source) β Found near blood vessels in connective tissue.
Basophils & Platelets β Store histamine in granules.
Main Sources of Serotonin and it effects
Platelets
Neuroendocrine cells (GI tract)
β Effects:
Vasoconstriction β Role in inflammation unclear.
Neurotransmitter function β Important in the GI tract and CNS
Triggers for Release of Histamine
1οΈβ£ Physical injury (trauma, cold, heat) β Mechanism unknown.
2οΈβ£ Allergic reactions β IgE binds antigens, triggering mast cell degranulation.
3οΈβ£ Complement activation β C3a & C5a (anaphylatoxins) stimulate histamine release.
4οΈβ£ Neuropeptides & cytokines β Substance P, IL-1, IL-8 can trigger release.
Effects of Histamine
Vasodilation β Expands arterioles.
Increased vascular permeability β Causes endothelial gaps in venules, leading to swelling (edema).
Smooth muscle contraction β Affects airways and intestines.
What is Arachidonic Acid (AA)? and how is it released?
β‘ Derived from dietary sources or synthesized from the essential fatty acid linoleic acid.
β‘ Stored in membrane phospholipids as an esterified precursor.
β Stimuli like mechanical, chemical, and physical injury or inflammatory mediators (e.g., C5a) trigger its release.
β Released from membrane phospholipids by phospholipase Aβ.
What are eicosanoids? and what enzymes are required for eicosanoids synthesis?
β‘ Bioactive lipid mediators derived from 20-carbon AA
β Cyclooxygenases (COX-1 & COX-2) β Produce prostaglandins (PGs).
β Lipoxygenases β Produce leukotrienes & lipoxins.
what is the function of Eicosanoids
Eicosanoids regulate every step of inflammation via G proteinβcoupled receptors.
What are COX-1 & COX-2?
β‘ Cyclooxygenase (COX) enzymes convert AA into prostaglandins.
π¬ COX-1 (Constitutive & Homeostatic)
β Expressed in most tissues.
β Maintains fluid & electrolyte balance (kidneys).
β Provides cytoprotection (GI tract).
β Also induced in inflammatory responses.
π¬ COX-2 (Inducible & Inflammatory-Specific)
β Primarily expressed in inflammatory cells.
β Induced during inflammation.
β Major target for anti-inflammatory drugs.
What are the major prostaglandins (PGs)?
β‘ Lipid mediators involved in vascular & systemic inflammation responses.
π¬ Important Prostaglandins:
β PGIβ (Prostacyclin) β Vasodilator, inhibits platelet aggregation.
β TxAβ (Thromboxane A2) β Vasoconstrictor, promotes platelet aggregation.
β PGDβ & PGEβ β Vasodilation, increased permeability, leading to edema.
β PGEβ β Involved in pain (hyperalgesia) & fever (cytokine-induced fever).
what will imbalance of PGI2 and TxA2 contribute to
Imbalance of PGIβ & TxAβ may contribute to thrombus formation in coronary & cerebral blood vessels.
What are leukotrienes? and what are the important leukotrienes?
β‘ AA-derived mediators produced by leukocytes & mast cells via lipoxygenase enzymes.
β‘ Regulate vascular reactions, smooth muscle contraction, and leukocyte recruitment.
β LTBβ β Potent chemotactic agent for neutrophils.
β LTCβ, LTDβ, LTEβ β Cause vasoconstriction, bronchospasm, and increased vascular permeability.
β Leukotrienes are stronger than histamine in causing bronchospasm & vascular permeability.
How do thromboxane A2 (TxA2) and prostacyclin (PGI2) differ?
π¬ TxAβ (Thromboxane A2):
β Produced by platelets (contain thromboxane synthase).
β Vasoconstrictor β Narrows blood vessels.
β Promotes platelet aggregation β Increases clot formation.
π¬ PGIβ (Prostacyclin):
β Produced by vascular endothelium (contains prostacyclin synthase).
β Vasodilator β Expands blood vessels.
β Inhibits platelet aggregation β Prevents excessive clotting.
What are lipoxins? and how are they formed
β‘ AA-derived mediators that resolve inflammation.
β‘ Suppress neutrophil chemotaxis & adhesion to endothelium.
π¬ Key Feature:
β Unique biosynthesis β Requires two cell types (e.g., neutrophils synthesize precursors, platelets convert them to active lipoxins)
What are cytokines? and what are the sources of cytokines?
β‘ Proteins produced by many cell types that mediate and regulate immune and inflammatory responses.
β Activated lymphocytes
β Macrophages
β Dendritic cells
β Endothelial, epithelial, and connective tissue cells
How are TNF and IL-1 different?
TNF (Tumor Necrosis Factor):
β Induced by TLR signaling & other microbial sensors.
β Enhances neutrophil responses to bacterial endotoxins.
β Promotes lipid & protein breakdown, leading to cachexia (weight loss, anorexia) in chronic disease.
IL-1 (Interleukin-1):
β Activated by the inflammasome (requires cleavage to be active).
β Stimulates fibroblasts to synthesize collagen.
β Induces Th17 responses, leading to acute inflammation.
What do TNF & IL-1 do? and sources of them?
β‘ Promote leukocyte recruitment by enhancing adhesion to the endothelium and facilitating migration.
β Macrophages & dendritic cells (primary producers)
β TNF also from T lymphocytes & mast cells
β IL-1 also from some epithelial cells
What are the main roles of TNF & IL-1 in inflammation?
1οΈβ£ Endothelial Activation:
β Induce expression of adhesion molecules (E-selectin, P-selectin, integrin ligands).
β Promote cytokine, chemokine, and eicosanoid production.
β Increase procoagulant activity of endothelial cells.
2οΈβ£ Activation of Leukocytes & Other Cells:
β TNF enhances neutrophil response to bacterial toxins.
β TNF stimulates macrophages to produce nitric oxide (NO) for microbicidal activity.
β IL-1 activates fibroblasts β increases collagen synthesis.
β IL-1 stimulates mesenchymal & synovial cell proliferation.
β IL-1 induces Th17 responses β promotes acute inflammation.
3οΈβ£ Systemic Acute-Phase Response:
β TNF, IL-1, & IL-6 induce fever, leukocytosis, and acute-phase protein production.
β TNF regulates metabolism β promotes lipid & protein mobilization, suppresses appetite (cachexia in chronic disease).
How do TNF & IL-1 contribute to chronic diseases?
β Overproduction causes sustained inflammation in autoimmune diseases like:
Rheumatoid arthritis (RA)
Psoriasis
Inflammatory bowel disease (IBD
TNF Inhibitors (Therapeutic Use):
β TNF antagonists (e.g., Infliximab, Etanercept, Adalimumab) are highly effective in chronic inflammatory diseases.
β Major side effect: Increased risk of mycobacterial infections (e.g., tuberculosis) due to weakened macrophage response.
Why donβt TNF or IL-1 inhibitors work for sepsis?
β Systemic inflammatory response syndrome (SIRS) due to cytokine storm.
β TNF & IL-1 contribute, but other cytokines also play major roles.
β Blocking one cytokine alone does not stop systemic inflammation.
How do cytokine roles differ in acute vs. chronic inflammation?
Acute Inflammation Cytokines:
β TNF, IL-1, IL-6 β Promote neutrophil recruitment, fever, vascular changes.
β Chemokines β Direct leukocyte migration.
Chronic Inflammation Cytokines:
β IL-12 β Stimulates T cells (Th1 response) & macrophage activation.
β IFN-Ξ³ β Enhances macrophage function.
β IL-17 β Drives neutrophil recruitment in persistent inflammation.
What are chemokines? and what is the function?
β‘ Small proteins (8β10 kDa) that act as chemoattractants for leukocytes
1οΈβ£ Recruit leukocytes to inflammation sites.
2οΈβ£ Organize immune cells within tissues (homeostatic function).
What are C-X-C chemokines?
β‘ Have one amino acid between the first two of four conserved cysteine residues.
π¬ Key Features:
β Mainly attract neutrophils.
β IL-8 (CXCL8) is a prototype member.
π¬ IL-8 (CXCL8) Production:
β Secreted by activated macrophages, endothelial cells, and other cells.
β Induced by microbial products, IL-1, and TNF.
π Key Function:
β Activates and attracts neutrophils.
β Limited effects on monocytes & eosinophils.
How do chemokines interact with receptors? and what its relation to HIV
β‘ Bind to seven-transmembrane G proteinβcoupled receptors.
π¬ Key Features:
β Receptors exhibit overlapping ligand specificity.
β Leukocytes express multiple chemokine receptors.
π Key Clinical Insight:
β HIV uses chemokine receptors (CXCR4 & CCR5) as coreceptors for viral entry.
β Blocking CCR5 (e.g., with Maraviroc) prevents HIV from infecting cells.
what are the classification of chemokines?
1- C-X-C
2-CC
3-C
4- CX3C
What are C-C chemokines?
β‘ First two cysteine residues are adjacent.
π¬ Key Features:
β Attract monocytes, eosinophils, basophils, and lymphocytes.
β Less effective for neutrophils.
π¬ Key CC Chemokines:
MCP-1 (CCL2) β Monocyte chemoattractant protein.
Eotaxin (CCL11) β Selectively recruits eosinophils.
MIP-1Ξ± (CCL3) β Macrophage inflammatory protein.
What are C and CX3C chemokines?
π¬ C Chemokines (Lymphotactins β XCL1):
β Lack 1st and 3rd conserved cysteine residues.
β Target lymphocytes specifically.
π¬ CX3C Chemokines (Fractalkine β CX3CL1):
β Have 3 amino acids between the two cysteines.
β Only known member: Fractalkine (CX3CL1).
π Fractalkine (CX3CL1) β Two Forms:
1οΈβ£ Membrane-bound form β Induced on endothelial cells β Promotes monocyte & T cell adhesion.
2οΈβ£ Soluble form β Derived by proteolysis β Chemoattractant for monocytes & T cells.
What is IL-6?
β‘ A cytokine involved in local & systemic inflammation.
π¬ Source:
β Produced by macrophages & other cells.
π Key Functions:
β Induces acute-phase responses.
β Promotes fever & systemic inflammation.
π¬ Clinical Use of IL-6 Inhibitors:
β Tocilizumab (anti-IL-6 receptor) is used for:
Juvenile arthritis.
Severe COVID-19 cytokine storms.
What is IL-17?
β‘ A cytokine that promotes neutrophil recruitment.
π¬ Source:
β Mainly produced by T lymphocytes (Th17 cells).
π Key Function:
β Enhances neutrophil responses in inflammation.
π¬ Clinical Use of IL-17 Inhibitors:
β Secukinumab (anti-IL-17) is used for:
Psoriasis.
Other autoimmune diseases.
What are the two main functions of chemokines?
π¬ 1οΈβ£ Acute Inflammation:
β Induced by microbes & cytokines.
β Increase integrin affinity on leukocytes β Enhance adhesion to endothelium.
β Guide leukocytes to infection & injury sites (chemotaxis).
π¬ 2οΈβ£ Tissue Architecture Maintenance (Homeostasis):
β Constitutively produced to organize immune cells in tissues.
β Example: T & B cell localization in spleen & lymph nodes.
What is the complement system, and what are its main functions?
The complement system is a collection of plasma proteins involved in:
Host defense against microbes (part of innate & adaptive immunity).
Pathologic inflammatory reactions.
Activation results in:
Increased vascular permeability
Chemotaxis (immune cell attraction)
Opsonization (coating pathogens for phagocytosis)
What are the three pathways of complement activation, and how is C3 cleaved?
Classical Pathway β Triggered by C1 binding to antibody (IgG or IgM) bound to an antigen.
Alternative Pathway β Activated by microbial surface molecules (LPS, endotoxins), complex polysaccharides, or cobra venom (no antibody needed).
Lectin Pathway β Activated when mannose-binding lectin binds to microbial carbohydrates, directly activating C1.
Key Event: C3 Convertase Formation
C3 β C3a + C3b
C3a β Inflammatory response.
C3b β Opsonization, forms C5 convertase, leading to membrane attack complex (C5bβC9) formation.
What are the three major functions of the complement system?
β 1. Inflammation
C5a, C3a, and C4a β Histamine release β Vasodilation & increased permeability.
C5a β Chemoattractant for neutrophils, monocytes, eosinophils, basophils.
C5a β Activates lipoxygenase pathway, producing inflammatory mediators.
β 2. Opsonization & Phagocytosis
C3b & iC3b bind microbes β Enhance phagocytosis by neutrophils/macrophages.
β 3. Cell Lysis
Membrane Attack Complex (MAC) (C5bβC9) forms pores in microbial membranes β Cell lysis.
Kills Neisseria bacteria (MAC deficiency = increased risk of Neisseria infections).
How is the complement system regulated, and what diseases result from regulatory defects?
β Complement activation is tightly regulated to protect host tissues. Key regulatory proteins:
C1 Inhibitor (C1 INH) β Blocks C1 activation (classical pathway).
Deficiency β Hereditary angioedema (excessive complement activation).
Decay Accelerating Factor (DAF) & CD59 β Prevent C3 convertase formation and MAC formation, respectively.
Deficiency β Paroxysmal nocturnal hemoglobinuria (PNH) (RBC lysis due to uncontrolled complement activation).
Complement Factor H β Inhibits the alternative pathway by breaking down C3b.
Deficiency β Atypical hemolytic uremic syndrome (HUS) (complement deposits in glomerular vessels β platelet-rich thrombi).
Factor H polymorphisms β Age-related macular degeneration (vision loss in elderly).
What is Platelet-Activating Factor (PAF), and what are its effects on inflammation?
PAF is a phospholipid-derived mediator that was first discovered as a factor causing platelet aggregation, but it also has multiple inflammatory effects.
Produced by: Platelets
Basophils
Mast cells
Neutrophils
Macrophages
Endothelial cells
Effects:
Platelet aggregation π©Έ
Vasoconstriction & Bronchoconstriction π«
Vasodilation & Increased venular permeability (at low concentrations)
Secreted & cell-bound forms exist
How does the coagulation pathway contribute to inflammation?
A link between coagulation & inflammation is supported by the presence of protease-activated receptors (PARs) on leukocytes, which are activated by thrombin.
Thrombin (Key Enzyme in Coagulation) Role:
Cleaves fibrinogen β Produces fibrin (forms clot) π©Ή
Activates PARs on leukocytes
Major role: Platelet activation in clotting
Other Inflammatory Effects:
Fibrin cleavage products (fibrinopeptides) may stimulate inflammation
Many tissue injuries show both clotting & inflammation, making a direct cause-effect link difficult to establish
What are kinins, and what role does bradykinin play in inflammation?
Kinins are vasoactive peptides derived from kininogens through the action of kallikreins (specific proteases).
Effects of Bradykinin:
β Vascular permeability π©Έ
Smooth muscle contraction πͺ
Blood vessel dilation π₯
Pain induction π (when injected into skin)
Similar effects to histamine
Short-Lived Action:
Rapidly inactivated by kininase
Involved in allergic reactions (e.g., anaphylaxis π¨)
How is Bradykinin Produced?
Kallikrein enzyme cleaves high-molecular-weight kininogen which Produces Bradykinin
What are neuropeptides, and how do they influence inflammation?
Neuropeptides are small peptides secreted by:
Sensory nerves
Leukocytes
Examples of Neuropeptides:
Substance P predominant in lungs and GIT
Neurokinin A
Functions in Inflammation:
Pain transmission β‘
Increases vascular permeability π©Έ
Leukocytes have receptors for neuropeptides β βCross-talkβ between nervous & immune systems
Vagus nerve activation inhibits pro-inflammatory cytokines like TNF
What are the general morphologic features of acute inflammation?
Dilation of small blood vessels
Accumulation of leukocytes and fluid in the extravascular tissue.
Patterns vary depending on severity, cause, and tissue involved.
What characterizes serous inflammation?
Exudation of cell-poor fluid into spaces created by cell injury or into body cavities (peritoneum, pleura, pericardium).
Fluid typically does not contain microbes or large numbers of leukocytes.
Common example: Skin blisters from burns or viral infections.
Effusion: Fluid accumulation in body cavities, which can occur in noninflammatory conditions (e.g., heart failure).
What occurs during fibrinous inflammation?
Increased vascular permeability allows fibrinogen to escape, forming fibrin in the extracellular space.
Common in the lining of body cavities (meninges, pericardium, pleura).
Histology: Eosinophilic meshwork of fibrin threads.
If unresolved, fibrin can lead to scarring and fibrous thickening (e.g., in the pericardium).
What is purulent inflammation, and what is an abscess?
Purulent inflammation: Characterized by pusβan exudate of neutrophils, necrotic cells, and edema fluid.
Abscess: Localized collection of pus in a confined space, often caused by pyogenic bacteria (e.g., staphylococci).
Histology: Central liquefied necrotic region surrounded by preserved neutrophils and vascular dilation, indicating chronic inflammation and repair.
What is an ulcer, and where do they commonly occur?
Ulcer: Local defect or excavation caused by the shedding of necrotic tissue.
Common in the mucosa (mouth, stomach, intestines) and skin (especially in the lower extremities in conditions like diabetes).
Peptic ulcers: Characterized by acute and chronic inflammation, with polymorphonuclear infiltration and fibroblastic proliferation
What are the typical outcomes of acute inflammation?
Resolution: Inflammation ends with restoration of normal tissue when injury is minor or short-lived.
Healing by fibrosis (scarring): Occurs when thereβs substantial tissue destruction or non-regenerating tissue.
Progression to chronic inflammation: Happens if the injury persists or the healing process is disrupted.
morphologic changes in Acute inflammation
1-Serous inflammation
2- Fibrinous inflammation
3- Purulent (suppurative inflammation and abscess)
4- Ulcers
What is chronic inflammation?
A prolonged response (weeks to months) where inflammation, tissue injury, and repair coexist.
It may follow acute inflammation or start as a slow, low-grade response without preceding acute signs.
Lymphocyte & Macrophage Interactions
Macrophages activate T cells (via antigen presentation & IL-12).
β‘ T cells activate macrophages (via cytokines), forming a self-sustaining loop.
π This cycle fuels chronic inflammation & may result in granuloma formation (seen in TB & sarcoidosis).
What are the causes of chronic inflammation?
Persistent Infections
1- Caused by difficult-to-eradicate microorganisms (e.g., mycobacteria, viruses, fungi, parasites).
Can lead to delayed-type hypersensitivity and sometimes granulomatous inflammation.
Example: Chronic lung abscess from unresolved acute bacterial infection.
2- π Hypersensitivity Diseases
Autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis) due to immune attacks on self-tissues.
Inflammatory bowel disease from unregulated immune response against microbes.
Allergic diseases (e.g., bronchial asthma) from reactions to harmless environmental antigens.
Often show mixed acute and chronic inflammation, with fibrosis in later stages.
3- β οΈ Prolonged Exposure to Toxic Agents
Exogenous toxins (e.g., inhaled silica β silicosis π«).
Endogenous toxins (e.g., cholesterol deposition in arteries β atherosclerosis π₯).
What are the key morphologic features of chronic inflammation?
π¬ Mononuclear Cell Infiltration β Macrophages, lymphocytes, plasma cells.
π₯ Tissue Destruction β Caused by persistent injury or inflammatory cells.
π οΈ Attempts at Healing β Fibrosis & angiogenesis (new blood vessel formation).
Where do macrophages come from?
Monocytes (in blood) β Migrate into tissues β Differentiate into macrophages.
Tissue macrophages persist for months to years.
πΊοΈ Specialized Macrophages in Organs
π¦ Kupffer cells (liver)
π« Alveolar macrophages (lungs)
π§ Microglial cells (brain)
π©Έ Sinus histiocytes (spleen & lymph nodes)
What are macrophages, and why are they important in chronic inflammation?
Main immune cells in chronic inflammation, responsible for:
πΉ Destroying invaders & damaged tissue (phagocytosis).
ποΈ Initiating tissue repair (scar formation & fibrosis).
π’ Secreting inflammatory mediators (cytokines: TNF, IL-1, chemokines, eicosanoids).
π Activating T cells β Sets up a feedback loop that sustains inflammation.
How do macrophages contribute to chronic inflammation?
π₯ Eliminate microbes & dead tissue (like neutrophils).
π οΈ Trigger tissue repair (fibrosis & scarring).
π£ Amplify inflammation (by releasing TNF, IL-1, and other mediators).
π Interact with T cells β Continues immune response.
How do macrophages get activated, and what are their two functional types?
1οΈβ£ π₯ Classical (M1) Activation
π¦ Induced by: Microbial products (e.g., endotoxins), IFN-Ξ³ (from T cells), foreign particles.
π― Function:
π« Kills microbes (produces NO & lysosomal enzymes).
π’ Pro-inflammatory (secretes cytokines like TNF & IL-1).
π‘οΈ First-line defense in infections.
2οΈβ£ π± Alternative (M2) Activation
π‘ Induced by: IL-4, IL-13 (from T cells).
π― Function:
π Suppresses inflammation.
ποΈ Promotes tissue repair & fibrosis.
β Not microbicidal.
π Balance between M1 & M2 macrophages determines whether inflammation persists or resolves!
π‘οΈ CD4+ T Cell Subsets & Their Roles
1οΈβ£ Th1 Cells
πΉ Secrete IFN-Ξ³ β Activates macrophages (M1) for killing microbes.
2οΈβ£ Th2 Cells
π± Secrete IL-4, IL-5, IL-13 β
π¦ Recruit eosinophils (for parasitic defense).
π Activate M2 macrophages (for tissue repair & fibrosis).
3οΈβ£ Th17 Cells
π¨ Secrete IL-17 β Attract neutrophils & monocytes for inflammation.
π Th1 & Th17 = Defense against bacteria & viruses + Autoimmune diseases.
π Th2 = Defense against parasites + Allergic reactions.
What role do eosinophils play in chronic inflammation?
π Eosinophils are prominent in IgE-mediated immune reactions (allergies πΏ) and parasitic infections πͺ±.
π Key Features:
Receptor: Express CCR3 receptor for eotaxin (chemokine that recruits eosinophils).
Toxic granules contain major basic protein (MBP) β‘ β kills helminths but also damages host epithelial cells ποΈ.
Involved in chronic conditions like bronchial asthma π¬οΈ.
What is the function of eosinophils in chronic inflammation?
π’ B lymphocytes are activated by antigens and differentiate into plasma cells, which produce antibodies π‘οΈ.
π Functions:
Antibodies target persistent foreign antigens π¦ or self-antigens (in autoimmune diseases π€).
Tertiary lymphoid organs form in some chronic inflammations (e.g., rheumatoid arthritis, Hashimoto thyroiditis).
Do neutrophils participate in chronic inflammation?
Recruited by: Persistent microbes π¦ & cytokines from activated macrophages & T cells.
Seen in:
Chronic bacterial infections like osteomyelitis π¦΄.
Lung damage due to smoking π¬ and other irritants.
This pattern is called βacute on chronicβ inflammation, where neutrophils persist in long-term inflammation
How do mast cells contribute to chronic & allergic inflammation?
π΅ Mast cells are present in acute & chronic inflammation, mainly in connective tissues.
π Key Features:
Receptor: Express FcΞ΅RI, a high-affinity receptor for IgE antibodies.
Granules contain: Histamine, prostaglandins, & cytokines β Trigger vasodilation, permeability, and smooth muscle contraction π.
Immediate hypersensitivity reactions (e.g., anaphylaxis π¨ from food, insect venom, drugs).
In chronic inflammation, they secrete cytokines that amplify inflammation.
What is the role of B lymphocytes in chronic inflammation
cells & plasma cells produce antibodies π‘οΈ against microbes or self-antigens.
ποΈ Can form tertiary lymphoid organs in chronic diseases (e.g., rheumatoid arthritis π€).
What is granulomatous inflammation, and why does it occur?
π΅ Granulomatous inflammation is a chronic inflammation characterized by clusters of activated macrophages, often with T lymphocytes and sometimes necrosis.
π Purpose:
It is a cellular attempt to contain difficult-to-eradicate agents βοΈ.
Strong T cell activation β Activates macrophages β May damage normal tissue.
Macrophages transform into:
Epithelioid cells ποΈ (large cytoplasm, epithelial-like).
Multinucleated giant cells π (fusion of macrophages)
Types of Granulomas
1οΈβ£ Foreign Body Granulomas
β What causes foreign body granulomas, and how do they form?
π Caused by inert foreign materials (do not elicit T cell immune response) βπ¦ .
π Examples:
Talc (IV drug use) π
Sutures πͺ‘
Other fibers
π Histologic Features:
Epithelioid & giant cells surround foreign body ποΈ.
Foreign material in center, visible under polarized light β¨.
2οΈβ£ Immune Granulomas
β What causes immune granulomas, and how do they form?
π Induced by persistent T cellβmediated immune response against hard-to-eradicate agents.
π Mechanism:
Persistent microbes (e.g., Mycobacterium tuberculosis) π¦ .
Th1 cells secrete IFN-Ξ³ β Activates macrophages π₯.
Parasitic infections (e.g., Schistosomiasis) β Th2 cells & eosinophils πͺ±
Leprosy associated granuloma
1- Noncaseating granuloma with acid fast bacilli inside macrophage
Tuberculosis associated granuloma
1- caseating granuloma (tubercle), consist of epithiloid cells, fibroblasts, langerhans giant cells, caseous necrosis
Syphilis associated granuloma
caused by treponema pallidum and causes Gumma ( wall of histocytes, plasma inflitrate, and necrotic centers with preserved cells outlien)
Cat-Scratch disease assocaited granuloma
caused by gram-negative bacillus and includes rounded granulomas with debris, neutrophils and few giant cells
Sarcoidosis assocaited granuloma
noncaseating granuloma with many activated macrophages
Crohns disease assocaited granuloma
Noncaseating granuloma in intestine wall, chronic inflammtory infiltrate
How is granulomatous inflammation diagnosed?
Acid-fast stains π¬ β Detect Mycobacterium tuberculosis π¨.
Culture methods π¦ β Used for TB & fungal infections π.
PCR (polymerase chain reaction) 𧬠β Detects Mycobacterium tuberculosis.
Serology π©Έ β Used in Syphilis.
What is the acute-phase response?
systemic reaction to inflammation, driven by cytokines (TNF, IL-1, IL-6, IFNs).
π Caused by:
Infections (e.g., viral, bacterial) π¦
Tissue injury π©Έ
Autoimmune diseases β‘
What causes fever during inflammation?
Pyrogens (fever-inducing substances) π₯
Exogenous: Bacterial products (e.g., LPS) π¦
Endogenous: Cytokines (IL-1, TNF)
Cyclooxygenase activation β β Prostaglandin (PGE2)
PGE2 acts on hypothalamus π§ β Raises body temperature.
π Effects:
Vasoconstriction β β Heat loss π₯Ά.
Muscle contraction & brown fat metabolism β Heat generation π₯.
π Fever treatment:
NSAIDs (e.g., aspirin) β Block prostaglandin synthesis β PGE2
What happens to white blood cells during inflammation?
Normal WBC: ~4,000β10,000/mL
π Leukocytosis: WBC count β to 15,000β20,000/mL (can reach 100,000/mL in extreme cases = leukemoid reaction).
What happens in severe bacterial infections (sepsis)?
Massive cytokine release (TNF, IL-1) β Leads to:
Disseminated Intravascular Coagulation (DIC) β Uncontrolled clotting π©Έ.
Hypotensive shock β Low BP π₯.
Metabolic disturbances (insulin resistance, hyperglycemia) π¬.
π **This severe systemic response is called Septic Shock β οΈ.
Types of Leukocytosis & Causes:
1- Neutrophilia (inc neutrophils) β> bacterial infection
2- Lymphocytosis ( increased lymphocytes) β> viral infections ( mononucleosis, mumps, measles)
3- Eosinophilia (inc eosinophils) β> parasite ifnection and allergies
4- Leukopenia (dec WBCs) β> Typhoid feverm rickettsia, viruses, protoza
What are acute-phase proteins, and what do they do?
Plasma proteins synthesized by the liver in response to inflammation (IL-6, IL-1, TNF).
π Key Proteins:
C-reactive protein (CRP) π©Ί β Opsonization & complement activation.
Serum amyloid A (SAA) π‘οΈ β Binds microbial cell walls.
Fibrinogen π©Έ β Promotes Rouleaux formation of RBCs, β ESR (erythrocyte sedimentation rate).
π Clinical Relevance:
β CRP = Inflammation (e.g., myocardial infarction risk β€οΈ).
Chronic SAA elevation = Secondary amyloidosis (protein buildup in organs).
Hepcidin β Iron availability β Anemia of chronic disease π.
Thrombopoietin β Platelet production β Thrombocytosis π©Έ.
Systemic Effects of Inflammation
Common Symptoms & Mechanisms:
β Heart rate (tachycardia) & β Blood pressure (hypertension) β€οΈ.
β Sweating (redirected blood flow to deeper vascular beds) π«π¦.
Chills (search for warmth) & Rigors (shivering) βοΈ.
Anorexia (loss of appetite), fatigue, and drowsiness π β Cytokine effects on the brain.
Systemic effects of inflammation
1- Fever
2- Elevated acute phase protiens
3- Leukocytosis
4- Inc PR,, BP, Dec sweating, rigors, chills, anorexia
5- High TNF and IL1 incase of spesis
When does scarring occur?
If regeneration is not possible due to severe injury or loss of supporting structures.
π Steps in Scar Formation:
1οΈβ£ Inflammation β Clears dead cells & microbes π₯.
2οΈβ£ Fibroblast activation β Connective tissue deposition π§±.
3οΈβ£ ECM remodeling β Stable fibrous scar.
Restores structural integrity but not full function βοΈ.
Seen in heart (myocardial infarction), lungs, liver, kidney π«
What is tissue repair?
Two main processes:
1οΈβ£ Regeneration β Restores damaged cells to their normal state.
2οΈβ£ Scarring (Fibrosis) β Replaces damaged tissue with connective tissue.
What is regeneration?
The replacement of damaged cells by proliferation of surviving cells & stem cells.
π Occurs in:
Liver (Hepatocytes can regenerate) π·
Epithelial tissues (Skin, Intestine) π₯
π Regeneration Mechanism:
1οΈβ£ Surviving differentiated cells proliferate.
2οΈβ£ Stem cells replenish lost cells.
3οΈβ£ Tissue returns to normal structure & function.
What is tissue regeneration?
The process of replacing injured cells & tissues via cell proliferation π.
π Key Requirements:
Growth factors (GFs) π β Stimulate cell division.
Extracellular matrix (ECM) integrity ποΈ β Provides structural support.
Tissue stem cells π± β Generate new cells
Differance between fibrosis and organization
1- Fibrosis is chronic depositon of collagen in organs seen in liver cirrhosis, lung fibrosis and kidney scarring
2- Organization is fibrosis occuring in tissue exudate seen in organizing pneumonia in lungs
Classification of Tissues Based on Regenerative Capacity
1- labile cells: high regenration and include skin, GI epithelium, BM, urinary tract
2- Stable, Limited generation and divide only if needed and found in G0 phase include kidney, pancrease, fibroblasts, endothelial cells and Liver ( not limited generation)
3- Permanent: very limited include brain neurons, heart muscles and skeletal muscles
What are stable tissues?
Cells that are normally quiescent (G0 phase) but can divide after injury
Parenchymal cells (Liver, kidney, pancreas π·).
Endothelial cells (Blood vessels π©Έ).
Fibroblasts & smooth muscle cells (Important in wound healing).
What are labile tissues?
Examples:
Hematopoietic cells (Bone marrow π©Έ).
Stratified squamous epithelium (Skin, oral cavity, vagina, cervix π₯).
Cuboidal epithelium (Ducts of exocrine glands β salivary glands, pancreas).
Columnar epithelium (GI tract, uterus, fallopian tubes π½οΈ).
Transitional epithelium (Urinary tract π½).
Liver Regeneration from Progenitor Cells
When hepatocyte proliferation is impaired (e.g., chronic liver injury, cirrhosis) β.
Oval cells (liver progenitor cells) step in to generate new hepatocytes.
Found in Canals of Hering
What are permanent tissues?
Neurons π§ (Brain, spinal cord).
Cardiac muscle cells π« (Heart).
Skeletal muscle cells πͺ (Some repair via satellite cells, but limited).
Priming Phase
Hepatocytes become responsive to growth factors π’.
π¦ Key Player:
IL-6 (produced by Kupffer cells)
What makes the liver special in regeneration?
The liver can regenerate up to 90% after injury or surgery β¨
1οΈβ£ Hepatocyte proliferation (Primary mechanism) π
Triggered by cytokines & growth factors π’.
Almost all hepatocytes re-enter the cell cycle π.
Occurs after partial hepatectomy (surgical removal of liver tissue).
2οΈβ£ Progenitor cell repopulation (Backup mechanism) π±
Activated when hepatocyte proliferation is impaired (e.g., chronic liver injury).
Progenitor cells (βOval cellsβ) help generate new hepatocytes.
Located in Canals of Hering (where bile canaliculi connect to bile ducts).
Growth Factor Phase
Hepatocytes enter the cell cycle (G0 β G1 β S phase) π.
π¦ Key Players:
HGF (Hepatocyte Growth Factor) π₯.
TGF-Ξ± (Transforming Growth Factor-alpha) ποΈ
Replication Phase
Hepatocytes multiply, followed by replication of other liver cells ποΈ.
π¦ Other proliferating cells:
Kupffer cells (macrophages) π¦ .
Endothelial cells (blood vessels) π©Έ.
Stellate cells (ECM remodeling) ποΈ.
π¬ Key Molecules:
Transcription factors βοΈ.
Cell cycle regulators π.
Termination Phase
ell division stops, and hepatocytes return to quiescence (G0) π¦.
π¦ Key Player:
TGF-Ξ² (Transforming Growth Factor-beta) π (anti-proliferative signal!).
what are the phases of liver generation
1-Priming
2-Replication
3- Termination
βοΈIL-6 primes hepatocytes to respond to growth factors π.
βοΈ HGF & TGF-Ξ± push hepatocytes into mitosis π.
βοΈ TGF-Ξ² stops the process & signals return to quiescence π.
What happens if tissue repair cannot occur by regeneration alone?
The injured cells are replaced by connective tissue, leading to scar formation.
How is scar formation different from regeneration?
Regeneration restores tissue structure, while scar formation βpatchesβ the damaged area without fully restoring function.
Steps in Scar Formation:
π©Έ Hemostasis (Immediate Response)
π¨ Within minutes, a platelet plug forms to stop bleeding & provide a scaffold for repair.
π₯ Inflammation (6-48 hours)
π¦ Neutrophils & Monocytes migrate via chemotaxis (complement activation, platelet-derived mediators).
π Function: Remove microbes & necrotic debris.
π οΈ As cleanup finishes, inflammation resolves.
π Cell Proliferation (~Up to 10 days)
π Various cell types proliferate & migrate to repair tissue:
β‘οΈ Epithelial cells β Respond to growth factors & cover the wound.
β‘οΈ Endothelial cells & Pericytes β Form new capillaries (angiogenesis π©Έ).
β‘οΈ Fibroblasts β Lay down collagen fibers for scar formation.
π± Granulation Tissue Formation:
𧱠Granulation tissue = Fibroblasts + New Capillaries + Macrophages
π©Ή Appears soft, pink, and granular under a scab.
π¬ Histology: Thin-walled capillaries, fibroblasts, loose ECM, macrophages.
π οΈ Fills the wound (amount depends on injury size & inflammation).
𧱠Connective Tissue Deposition β Fibrous Scar
β‘οΈ Granulation tissue is gradually replaced by collagen.
β‘οΈ Forms a dense, fibrous scar that stabilizes tissue.
Macrophages function in scare formation
M2 Macrophages β Clear debris, secrete growth factors, and stimulate fibroblasts.
What is angiogenesis?
πΉ Formation of new blood vessels from existing ones.
πΉ Essential for wound healing, ischemia recovery, and tumor growth.
Steps of Angiogenesis
π©Έ 1. Vasodilation & Permeability Increase
π’ VEGF stimulates NO release, leading to vasodilation & increased permeability
π 2. Basement Membrane Breakdown
π οΈ Pericytes detach + ECM breakdown β Creates space for new vessel sprout.
π 3. Endothelial Cell Migration
πΆ Endothelial cells move toward injury site, guided by VEGF & integrins.π 4. Endothelial Cell Proliferation
π¬ 4. New cells grow behind the tip of migrating cells.
π©Ή 5. Capillary Tube Formation
π Endothelial cells remodel into functional capillaries.
π 6. Maturation & Stabilization
βοΈ Pericytes (small vessels) & smooth muscle cells (larger vessels) stabilize new vessels.
βοΈ PDGF recruits smooth muscle cells, while TGF-Ξ² suppresses endothelial growth & promotes ECM deposition.
π 7. Suppression of Growth & Finalization
π΅ Endothelial proliferation & migration stop, and basement membrane is deposited.
Key Growth Factors in Angiogenesis
π VEGF-A β Initiates angiogenesis, promotes migration, proliferation, & vasodilation (via NO).
π FGF-2 β Endothelial proliferation, macrophage & fibroblast migration, and epithelial wound healing.
π οΈ Angiopoietins (Ang1, Ang2) β Regulate vessel stability & maturation.
π PDGF β Recruits smooth muscle cells for vessel stabilization.
π TGF-Ξ² β Suppresses endothelial growth, enhances ECM deposition.
𧬠Other Important Players
𧩠Notch Signaling β Regulates vessel branching & spacing to ensure proper blood supply.
π ECM Proteins & Integrins β Provide structural support & guide endothelial migration.
βοΈ MMPs (Matrix Metalloproteinases) β Degrade ECM to allow vessel remodeling & extension.
How is connective tissue deposited during repair?
Two key steps:
β‘οΈ Fibroblast migration & proliferation into the injury site.
β‘οΈ ECM protein deposition (collagen, fibronectin) by fibroblasts.
πΉ Regulated by cytokines & growth factors β PDGF, FGF-2, TGF-Ξ² (mainly from M2 macrophages).
πΉ Mast cells & lymphocytes can also secrete factors that promote fibroblast activation.
Role of TGF-Ξ² in Connective Tissue Deposition
βοΈ Most important cytokine for ECM synthesis & deposition.
βοΈ Stimulates fibroblast migration & proliferation.
βοΈ Increases collagen & fibronectin production.
βοΈ Inhibits MMPs (matrix metalloproteinases) β Prevents ECM degradation.
βοΈ Anti-inflammatory function β Suppresses lymphocyte proliferation & limits inflammation.
βοΈ Contributes to fibrosis in lungs, liver, kidneys during chronic inflammation.
Maturation of the Scar steps
β‘οΈ Fibroblasts switch to a synthetic phenotype β More ECM deposition.
β‘οΈ New blood vessel formation decreases β Granulation tissue becomes a pale, avascular scar.
β‘οΈ Some fibroblasts become myofibroblasts β Contain actin filaments & contribute to scar contraction.
Remodeling of Connective Tissue
πΉ The final scar is shaped by a balance of ECM synthesis & degradation.
πΉ MMPs (Matrix Metalloproteinases) β Break down ECM to allow remodeling.
βοΈ MMP Types:
β‘οΈ Collagenases (MMP-1, MMP-2, MMP-3) β Degrade fibrillar collagen.
β‘οΈ Gelatinases β Break down amorphous collagen & fibronectin.
β‘οΈ Stromelysins β Degrade proteoglycans, laminin, fibronectin.
Tight Regulation of MMPs
βοΈ MMPs are secreted as inactive zymogens β Activated by proteases (e.g., plasmin) at injury sites.
βοΈ TIMPs (Tissue Inhibitors of MMPs) rapidly inhibit MMPs once remodeling is complete
What are the key factors that influence tissue repair?
Tissue repair is influenced by systemic (affecting the whole body) and local (affecting the wound site) factors. These include infection, diabetes, nutrition, steroids, mechanical stress, blood supply, foreign bodies, tissue type, and injury location.
How does infection affect wound healing?
Infection π¦ prolongs inflammation, increases local tissue injury, and delays healing.
Why does diabetes impair tissue repair?
Poor circulation (ischemia) β Reduces oxygen & nutrient supply.
Immune dysfunction β Increases infection risk.
Metabolic imbalances β Affect collagen synthesis & fibroblast activity.
How does nutrition affect healing?
Protein deficiency β Inhibits fibroblast function & collagen synthesis.
Vitamin C deficiency π β Impaired collagen formation (scurvy-like effects).
What effect do glucocorticoids (steroids) have on healing?
Reduce inflammation but inhibit TGF-Ξ², leading to weaker scars.
Used in corneal infections to prevent scarring & opacity.
What are some local factors that affect wound healing?
Mechanical stress (torsion, pressure) β Wound dehiscence (splitting open).
Poor blood supply (peripheral vascular disease, varicose veins) β Delayed healing.
Foreign bodies (glass, steel, bone fragments) β Sustain chronic inflammation.
Tissue type & injury severity β
Stable/labile cell tissues β Can regenerate completely.
Permanent cell tissues (neurons, cardiac muscle) β Heal with fibrosis/scarring.
How does the location of an injury affect healing?
In tissue spaces (pleural, peritoneal, synovial cavities):
Small exudates β Cleared via enzymatic digestion (resolution) β Full tissue restoration.
Large exudates β Granulation tissue replaces exudate β Scar formation (organization).
What are the two major types of skin wound healing?
1οΈβ£ Healing by First Intention (Primary Union) β Occurs in small, clean wounds (e.g., surgical incisions), mainly through epithelial regeneration with minimal scarring.
2οΈβ£ Healing by Second Intention (Secondary Union) β Occurs in larger wounds with significant tissue loss, requiring more granulation tissue, wound contraction, and fibrosis.
What are the key steps in first intention healing?
π©Έ Blood Clot Formation β Stops bleeding, provides a scaffold for migrating cells.
π¦ Neutrophil Infiltration (Day 1-2) β Clears debris; epithelial cells migrate to cover the wound.
π Macrophage Infiltration (Day 3-5) β Promotes angiogenesis, ECM deposition, and fibroblast activation.
πΏ Granulation Tissue Peak (Day 5) β New blood vessels & fibroblasts fill the wound.
𧩠Collagen Deposition & Remodeling (Week 2-4) β Fibroblasts lay down collagen, scar forms.
πͺ Scar Maturation (1 Month+) β Epidermis normalizes, tensile strength increases.
How does second intention healing differ from first intention?
Larger wound & tissue loss β Requires more inflammation & granulation tissue.
More necrotic debris β Stronger inflammatory response.
More collagen deposition β Larger, thicker scar formation.
Wound contraction (via myofibroblasts) reduces wound size by 5-10% over 6 weeks.
How strong is a healed wound compared to normal skin?
Sutured wounds β 70% strength initially.
By 3 months β 70-80% of normal tensile strength.
Never fully regains original strength.
What is fibrosis, and how does it affect organs?
π Fibrosis = Excess collagen & ECM deposition β Leads to organ dysfunction/failure.
π©Ί Examples of Fibrotic Diseases:
Liver Cirrhosis π·
Pulmonary Fibrosis (Idiopathic, Radiation, Pneumoconioses) π«
Systemic Sclerosis (Scleroderma) ποΈ
End-Stage Kidney Disease π°
Constrictive Pericarditis β€οΈ
What are the three major types of abnormalities in tissue repair?
1οΈβ£ Deficient Scar Formation β Leads to chronic wounds & wound dehiscence.
2οΈβ£ Excessive Scar Formation β Results in hypertrophic scars, keloids, & excessive granulation tissue.
3οΈβ£ Contractures β Excessive wound contraction causing deformities & functional impairment.
What are the causes of chronic wounds?
𦡠Venous Leg Ulcers β Chronic venous hypertension (e.g., varicose veins, CHF) β Poor oxygen delivery β Non-healing ulcer.
π« Arterial Ulcers β Peripheral artery disease (atherosclerosis, diabetes) β Ischemia β Skin atrophy & necrosis.
π¦Ά Diabetic Ulcers β Vascular disease, neuropathy, metabolic abnormalities, infections β Necrosis & non-healing wounds on feet.
ποΈ Pressure Sores β Prolonged mechanical pressure (bedridden patients) β Local ischemia & necrosis.
π©Έ Wound Dehiscence = Surgical wound reopening due to obesity, malnutrition, infection, or vascular insufficiency.
What are hypertrophic scars and keloids?
π¦ Hypertrophic Scar β Raised scar within wound boundaries, rich in myofibroblasts, but regresses over time.
π₯ Keloid β Scar extends beyond the wound, does not regress, and may be genetic (more common in African Americans).
What is exuberant granulation tissue (proud flesh)?
π± Excessive granulation tissue forms above the skin level, blocking re-epithelialization.
β‘ Needs removal (cautery or surgical excision) for normal healing.
What are desmoids/aggressive fibromatoses?
π¦ Rare fibroblast overgrowths after injury or surgery.
π Not malignant but can invade local tissue.
π High recurrence rate after excision.
What is a contracture, and where does it commonly occur?
π Excessive wound contraction β Deformity & impaired movement.
π₯ Common after burns β Seen on palms, soles, anterior thorax.
𦡠Can restrict joint mobility.
