Inflammation | Anatomy2Medicine
Causes-of-Inflammation

Inflammation

 

  • ACUTE INFLAMMATION
  • Adhesion molecules
        • They are divided into three families:
  • Selectins
  • immunoglobulin-family adhesion proteins
          • integrins.
  • Selectins
          • induced by IL-1 and TNF
          • L-selectins (MCQ)
            • expressed on neutrophils
            • bind to endothelial mucin-like molecules such as GlyCam-1.
          • E- and P-selectins
            • expressed on endothelial cells
  • bind to oligosaccharides such as sialyl-Lewis X on the surface of leukocytes. (MCQ)
  • P-selectins
            • stored in endothelial Weibel-Palade bodies and platelet alpha granules, relocate to the plasma membrane after stimulation by mediators such as histamine and thrombin. (MCQ)
  • Immunoglobulin-family adhesion proteins
          • Intercellular adhesion molecules 1 and 2 (ICAM-1 and ICAM-2)
            • expressed on endothelial cells(MCQ)
            • bind to integrin molecules on leukocytes.
          • Vascular cell adhesion molecules (VCAMs)
            • expressed on endothelial cells
            • bind to integrin molecules on leukocytes.
        • Integrins.
          • include leukocyte LFA-1, MAC-1, and VLA-4(MCQ)
          • bind to endothelial immunoglobulin-family adhesion proteins
  • Vasoactive changes
        • These changes begin with a brief period of vasoconstriction
        • Vasoconstriction is  followed shortly by dilation of arterioles, capillaries, and
        • clinically manifest by redness and increased warmth of the affected area.
  • Increased capillary permeability
        • This results in leakage of proteinaceous fluid, which causes edema.
        • Causes include
  • contraction of endothelial cells in postcapillary venules
  • widening of interendothelial gaps
  • major endothelial damage involving arterioles, capillaries, and venules.
  • Types of inflammatory cells
        • Neutrophils
  • most prominent inflammatory cells in foci of acute inflammation during the first 24 hours.
          • Important causes of neutrophilia
  • bacterial infections
  • infarction.
  • There is often an increase in the proportion of less mature cells such as band neutrophils(MCQ)
  • The early release of neutrophils occur from the bone marrow postmitotic reserve pool.
  • monocytes-macrophages
  • After 2–3 days, neutrophils are replaced mainly by monocytes-macrophages (MCQ)
          • They are capable of engulfing larger particles
          • They  are longer-lived
          • They are capable of dividing and proliferating within the inflamed tissue.
          • Important causes of monocytosis (MCQ)
  • tuberculosis, brucellosis
  • typhus, and salmonella infection.
        • Lymphocytes
          • most prominent inflammatory cells in many viral infections
          • most prominent cells in chronic inflammation
        • Lymphocytosis
          • most often caused by viral infections such as  (MCQ)
  • influenza, mumps, rubella
  • infectious mononucleosis
  • certain bacterial infections such as (MCQ)
  • whooping cough
  • tuberculosis
        • Eosinophils
          • predominant inflammatory cells in allergic reactions and parasitic infestations
          • causes of eosinophilia include (MCQ)
  • allergies such as asthma, hay fever, and hives
  • parasitic infections
  • polyarteritis nodosa
            • Hodgkin lymphoma.
  • Mast cells and basophils
          • They are sources of histamine
          • Important causes of basophilia include (MCQ)
  • chronic myelogenous leukemia
  • myeloproliferative diseases.
  • Cellular response of leukocytes
        • Emigration
          • passage of inflammatory leukocytes between the endothelial cells into the adjacent interstitial tissue
          • Before emigration, circulating leukocytes from the central blood flow move toward the endothelial surface.
  • Margination
          • occurs as leukocytes localize to the outer margin of the blood flow adjacent to the vascular endothelium.
  • Pavementing
          • occurs as leukocytes line the endothelial surface.
        • Rolling (or tumbling)
          • mediated by the action of endothelial selectins loosely binding to leukocytes
          • it produces a characteristic “rolling” movement of the leukocytes along the endothelial surface.
  • Adhesion
          • occurs as leukocytes adhere to the endothelial surface
          • mediated by the interaction of integrins on leukocytes binding to immunoglobulin-family adhesion proteins on endothelium. (MCQ)
        • Transmigration
          • movement of leukocytes across the endothelium
          • mediated by platelet endothelial cell adhesion
        • Chemotactic factors for neutrophils (MCQ)
  • Products from bacteria
  • C5a
  • leukotriene B4 (LTB4)
  • hydroxyeicosatetraenoic acid (HETE)
  • kallikrein
  • Phagocytosis
  • Neutrophils and monocytes-macrophages are the most important phagocytic cells.
  • Anatomic changes
  • internalization of the attached opsonized particle by pseudopodial extensions from the surface of the leukocyte, which enclose the foreign particle, forming an internalized vesicle, the phagosome.
  • Phagosomes fuse with cytoplasmic lysosomes and form phagolysosomes.
          • Phagolysosome formation is associated with leukocytic degranulation.
  • Opsonization
        • This process facilitates phagocytosis
        • It is the coating of particulate material by substances referred to as opsonins, which immobilize the particles on the surface of the phagocyte.
        • The most important opsonins are (MCQ)
  • immunoglobulin G (IgG) subtypes
          • C3b, a complement component.
        • Fragments opsonized by IgG are bound to phagocytic cells by cell-surface receptors for the Fc portion of the IgG molecule. (MCQ)
        • Fragments opsonized by C3b bind to cellular receptors for C3b. (MCQ)
      • Intracellular microbial killing
  • Oxygen-dependent microbial killing
          • most important intracellular microbicidal process.
          • Phagocytosis initiates activity of the hexose monophosphate shunt
          • causes an oxidative burst and supplying electrons to an NADPH oxidase in the phagosomal membrane.
  • One of the products of the NADPH oxidase reaction is superoxide anion (O2·-)
          • superoxide anion (O2·-) is further converted to hydrogen peroxide (H2O2) by dismutation.
  • H2O2 may be further converted to the activated hydroxyl radical (OH·).
  • Myeloperoxidase-halide system of bacterial killing. (MCQ)
  • In the presence of the leukocyte enzyme myeloperoxidase and a halide ion such as chloride, H2O2 oxidizes microbial proteins and disrupts cell walls.
  • Oxygen-independent microbial killing
          • This process is much less effective than oxygen-dependent microbial killing.
          • This process is mediated by proteins, such as (MCQ)
  • lysozyme, lactoferrin
  • major basic protein of eosinophils
            • cationic proteins, such as
              • bactericidal permeability-increasing protein
              • defensins.
  • Exogenous and endogenous mediators of acute inflammation
      • Exogenous mediators
  • most often of microbial origin
        • formylated peptides of Escherichia coli are chemotactic for neutrophils
  • Endogenous mediators
        • are of host origin
  • Vasoactive amines
  • Histamine
  • liberated from basophils, mast cells, and platelets.
            • mediates the increase in capillary permeability associated with the contraction of endothelial cells in postcapillary venules that occurs with mild injuries. (MCQ)
  • Histamine is liberated from Basophils and mast cells by degranulation triggered by the following stimuli: (MCQ)
              • Binding of specific antigen to basophil and mast cell membrane-bound IgE (complement is not involved)
              • Binding of complement fragments C3a and C5a, anaphylatoxins, to specific cell-surface receptors on basophils and mast cells (specific antigen and IgE antibodies are not involved(MCQ)
              • Physical stimuli such as heat and cold
  • Cytokine IL-1 (MCQ)
              • Factors from neutrophils, monocytes, and platelets
  • Histamine is liberated from platelets by platelet aggregation and the release reaction, which can be triggered by endothelial injury and thrombosis or by platelet-activating factor (PAF).
            • PAF (MCQ)
              • derived from the granules of basophils and mast cells and from endothelial cells, macrophages, neutrophils, and eosinophils
              • it is acetyl-glyceryl-ether phosphorylcholine, also known as AGEPC. (MCQ)
              • PAF activates and aggregates platelets
  • It releases histamine and serotonin
              • It causes vasoactive and bronchospastic effects(MCQ)
  • It activates arachidonic acid metabolism.
  • Serotonin (5-hydroxytryptamine)
            • acts similar to histamine.
            • It is liberated from platelets.
  • Arachidonic acid metabolites
          • Phospholipase A2 stimulates the release of arachidonic acid from membrane phospholipids
          • The cyclooxygenase (cyclic endoperoxide) pathway
            • catalyzed by COX-1 and COX-2
            • This pathway is inhibited by aspirin
            • It yields thromboxanes and prostaglandins
            • thromboxane A2 (TxA2) in platelets(MCQ)
              • a powerful vasoconstrictor
              • platelet aggregant.
            • prostacyclin (PGI2) in endothelial cells, (MCQ)
              • a powerful vasodilator
              • inhibitor of platelet aggregation.
          • The lipoxygenase pathway
            • yields hydroperoxyeicosatetraenoic acid (HPETE) and its derivatives (MCQ)
              • 12-HPETE in platelets
              • 5-HPETE and 15-HPETE in leukocytes.
            • 5-HPETE in turn gives rise to HETE, a chemotactic factor for neutrophils.
            • 5-HPETE also gives rise to leukotrienes:
              • LTB4(MCQ)
                • a chemotactic factor for neutrophils
              • LTC4, LTD4, and LTE4(MCQ)
                • potent vasoconstrictors
  • bronchoconstrictors
  • mediators of increased capillary permeability
                • jointly referred to as the slow-reacting substance of anaphylaxis
            • 5-HPETE  also indirectly gives rise to lipoxins. LXA4 and LXB4 (MCQ)
              • inhibit polymorphonuclear neutrophils and eosinophils
              • activate monocytes and macrophages
              • lipoxins are involved in resolving inflammation
  • lipoxins are potential anti-inflammatory mediators that may have therapeutic value.
            • Cytokines
              • These are soluble proteins
  • interferon-γ (MCQ)
            • produced by T cells and natural killer cells
            • activates monocytes
          • cytokines IL-1 and TNF (MCQ)
            • secreted by monocytes-macrophages
            • induce acute phase responses, such as
              • Systemic effects of inflammation, including fever and leukocytosis
              • Hepatic synthesis of acute phase proteins, such as C-reactive protein, serum amyloid–associated protein, complement components, fibrinogen, prothrombin, α1-antitrypsin, α2-macroglobulin, ferritin, and ceruloplasmin
              • Synthesis of adhesion molecules
              • Neutrophil degranulation
  • reduce the thromboresistant properties of endothelium, thus promoting thrombosis.
  • Kinin system
          • initiated by activated Hageman factor (factor XIIa).
  • Factor XIIa links the kinin, coagulation, plasminogen, and complement systems.
            • Factor XIIa activates the intrinsic pathway of coagulation (MCQ)
            • Factor XIIa activates plasminogen (fibrinolytic) system(MCQ)
  • Activation of Kinin system in turn activates the complement cascade.
  • Kinin system
            • converts prekallikrein to kallikrein (a chemotactic factor).

 

  • It results in the cleavage, by kallikrein, of high-molecular-weight kininogen to bradykinin
  • Bradykinin
            • is a peptide that is nine amino acids in length
            • mediates vascular permeability, arteriolar dilation, and pain.
  • Complement system
          • consists of a group of plasma proteins
          • participate in immune lysis of cells
          • C3a and C5a (anaphylatoxins) (MCQ)
            • mediate degranulation of basophils and mast cells
            • cause release of histamine
  • C5a (MCQ)
  • Chemotactic
  • mediates the release of histamine from platelet-dense granules
            • induces expression of leukocyte adhesion molecules
            • activates the lipoxygenase pathway of arachidonic acid metabolism.
          • C3b is an opsonin. (MCQ)
  • C5b-9(MCQ)
            • Is the membrane attack complex
            • is a lytic agent for bacteria and other cells.
        • Nitric oxide
          • known as endothelium-derived relaxing factor(MCQ)
          • produced by endothelial cells.
          • stimulates relaxation of smooth muscle
          • plays a role in controlling vascular tone
          • It inhibits platelet aggregation
          • contributes to endothelial thromboresistance.
  • Hereditary defects that impair the acute inflammatory response
  • Deficiency of complement components
        • Notable deficiencies include C2, C3, and C5.
  • Defects in neutrophils
  • Chronic granulomatous disease of childhood
          • X-linked disorder (MCQ)
          • characterized by deficiency of NADPH oxidase activity and the oxidative burst(MCQ)
          • phagocytic cells can ingest but do not kill certain microorganisms.
  • Catalase-positive organisms are ingested but not killed(MCQ)
            • Pathophysiology
  • Staphylococcus aureus like organisms can destroy H2O2 generated by bacterial metabolism.
              • Because enzyme-deficient neutrophils cannot produce H2O2 , H2O2 is not available as a substrate for myeloperoxidase
              • Thus, the myeloperoxidase-halide system of bacterial killing fails.
          • Catalase-negative organisms are ingested and killed (MCQ)
            • Streptococci like organisms produce sufficient H2O2 to permit oxygen-dependent microbicidal mechanisms to proceed
            • In effect, the substrate for myeloperoxidase is produced by the bacteria, and the bacteria in a sense kill themselves.
  • Myeloperoxidase deficiency
          • Causes rarely  recurrent bacterial infections
          • often has little clinical consequence.
  • there is  a marked increase in susceptibility to infections with Candida albicans. (MCQ)
        • Chédiak-Higashi syndrome
          • autosomal recessive disorder (MCQ)
          • characterized by (MCQ)
  • neutropenia, albinism
            • cranial and peripheral neuropathy
          • a tendency to develop repeated infections.
          • It is marked by the presence of abnormal white blood cells(MCQ)
  • Functional abnormalities
              • abnormal microtubule formation, affecting movement
              • impaired chemotaxis and migration
            • Morphological abnormalities
  • caused by impaired membrane fusion of lysosomes
              • large cytoplasmic granules (representing abnormal lysosomes) in granulocytes, lymphocytes, and monocytes
              • large abnormal melanosomes in melanocytes(MCQ)
        • Leukocyte adhesion deficiency (LAD) types 1 and 2
          • associated with recurrent bacterial infections
          • LAD type 1 deficiency
  • caused by deficiency of β2-integrins. (MCQ)
    • LAD type 2 deficiency
  • caused by mutations in the gene that codes for fucosyltransferase, required for the synthesis of sialyl-Lewis X on neutrophils. (MCQ)

Mediators of inflammation

  • Vasoconstriction (MCQ)
      • TxA2
      • LTC4, LTD4, LTE4
      • PAF
  • Vasodilation (MCQ)
      • PGI2
      • PGD2, PGE2, PGF2α
      • Bradykinin
      • PAF
      • Nitric oxide
  • Increased vascular permeability (MCQ)
    • Histamine
    • Serotonin
    • PGD2, PGE2, PGF2α
    • LTC4, LTD4, LTE4
    • Bradykinin
    • PAF
  • Tissue repair
  • Labile cells (MCQ)
        • These cells divide actively throughout life to replace lost cells.
  • They are capable of regeneration after injury.
        • They include cells of the  (MCQ)
          • epidermis and gastrointestinal mucosa
          • cells lining the surface of the genitourinary tract
          • hematopoietic cells of the bone marrow.
  • Stable cells (MCQ)
        • Characteristically, these cells undergo few divisions
        • capable of division when activated
        • they can regenerate from G0 cells when needed. (MCQ)
        • They are also capable of regeneration following injury.
        • They include  (MCQ)
  • hepatocytes, renal tubular cells
        • parenchymal cells of many glands
        • numerous mesenchymal cells (e.g., smooth muscle, cartilage, connective tissue, endothelium, osteoblasts).
  • Permanent cells
        • incapable of division and regeneration
        • They include neurons and myocardial cells. (MCQ)
  • Cellular proliferation.
    • Platelet-derived growth factor (PDGF)
      • a competence factor
      • promotes the proliferative response of fibroblasts and smooth muscle cells on concurrent stimulation by progression factors (e.g., other growth factors).
      • PDGF promotes the synthesis of collagen. (MCQ)
      • synthesized by platelets and several other cells.
      • promotes the chemotactic migration of fibroblasts and smooth muscle cells.
      • PDGF is chemotactic for monocytes.
      • PDGF reacts with specific cell-surface receptors that have tyrosine kinase activity in their intracellular domains. (MCQ)
  • Epidermal growth factor (EGF)
      • It is a progression factor (MCQ)
      • promotes the growth of endothelial cells and fibroblasts, as well as epithelial cells.
  • Fibroblast growth factors (FGFs)
      • promote the synthesis of extracellular matrix protein (including fibronectin) by fibroblasts, endothelial cells, monocytes, and other cells.
    • Fibronectin
      • a glycoprotein
      • It is chemotactic for fibroblasts and endothelial cells.
      • It promotes angiogenesis(MCQ)
      • It links other extracellular matrix components (e.g., collagen, proteoglycans) and macromolecules (e.g., fibrin, heparin) to cell- surface integrins(MCQ)
      • Integrins mediate interactions between cells and extracellular matrix. (MCQ)
    • Transforming growth factors (TGFs)
      • TGF-α functions similarly to EGF.
      • TGF
        • a growth inhibitor for many cell types (MCQ)
        • aid in modulating the repair process
        • also a chemotactic factor for macrophages and fibroblasts.
    • Macrophage-derived growth factors (IL-1 and TNF)
  • promote the proliferation of fibroblasts, smooth muscle cells, and endothelial cells. (MCQ)