Inflammation #4 PDF

INFLAMMATION #4  INTRO:  There are 4 plasma derived systems (kinin, clotting & fibrinolytic cascade, and complement system  start by the activation of hagman factor (XII)  (++) of hagman factor by the attatchment to:  Platelets  basement membrane  collagn fibers. → formation of factor XIIa...

INFLAMMATION #4  INTRO:  There are 4 plasma derived systems (kinin, clotting & fibrinolytic cascade, and complement system  start by the activation of hagman factor (XII)  (++) of hagman factor by the attatchment to:  Platelets  basement membrane  collagn fibers. → formation of factor XIIa  Kinin System:  Hageman Factor (XII): activated at site of injury (platelets, BM, collagen), → XIIa.  XIIa helps in: Prekallikrein → Kallikrein  Kallikrein helps in: HMW kininogen → bradykinin  BRADYKININ effect: vascular dilatation, ↑ vascular permeability, bronchoconstriction, pain.  Inactivated by KININASES (short life).  Kallikrein: Chemotactic & factor XII (++) → amplify the cascade (autoactivation).  clotting system:  Process:  XIIa: activates (++) facror XI → XIa  XIa: (++) Factor X → Xa  Xa: ↑ vascular permeability  leukocyte migration (intermediate factor, participate in inflammation)  Xa: will convert factor II (prothrombin) → THROMBIN  THROMBIN: cleaves FIBRINOGEN (soluble protein) → FIBRIN (insoluble) clot.  Thrombin: Binds to PROTEASE-ACTIVATED RECEPTORS (PARS) expressed on platelets, ECs, SMCs     leading to: P-selectin mobilization Expression of integrin ligands Chemokine & PAF & NO production PGs production by activating cyclooxygenase-2  also lead to the production of fibrinopeptides: ↑ vascular permeability & chemotaxis.  Fibrinolytic system:  If the production of fibrin was uncontrolled → BVs will be thrombosed (blocked)  To stop it: fibrinolytic system  Process:     XIIa: will convert prekallikrein → kallikrein (activate the fibriolytic system) Kallikrein: will transform plasminogen → plasmin (end result) plasmin (act as an enzyme): degrade fibrin → fibrin split products plasmin:  cleaves C3 to C3a: Dilation & ↑ BVs permeability  activates XII  Fibrin split products (FSP): ↑ permeability (inflammation role of fibrin) Page | 0 Positive feedback  Complement System:  collection of soluble proteins & their membrane receptors  function mainly in host defense against microbes (IMMUNITY)  in pathologic inflammatory reactions (INFLAMMATION).  proteins will be activated by cleavage → (a: Small & b: Large)     More than 20 complement proteins, some of which are numbered C1 through C9. to generate a porelike MAC to punch holes in the membranes of attacking microbes. They function in both INNATE & ADAPTIVE immunity for defense against microbial pathogens. Several cleavage products of complement proteins are elaborated within the cascade that cause  ↑ vascular permeability  Chemotaxis  Opsonization (C3b).  Activation occurs via three pathways: The classic, alternative and Lectin pathway.  Classic pathway: Antigen-antibody complexes → activate C1       activated C1 → (++) C2 (cleaved into C2a & C2b) C2a → (++) C4 (cleaved into C4a & C4b). C4b + C2a → C3 convertase: convert C3 to C3a & C3b. C3b + C3 convertase → C5 convertase: convert C5 to C5a & C5b. C5b + C (6- 9) → membrane attack complex "MAC" (pole like structure) MAC: target the microbial membrane → lysis by holes → rupture of microbe & apoptosis  Alternative pathway:       Microbial surfaces polysaccharides → conversion of C3 to C3b Liver will produce some factors like factor B & Factor D Factor D → (++) Factor B (Ba & Bb) Bb + C3b → another C3 convertase (‫ )بختلف عن الي ذكرناه قبل شوي‬--stabilized by properdin--. C3 convertase: convert C3 to C3a & C3b C3b + C3 convertase → formation of C5 convertase + ‫والتكملة معروفة‬. Page | 1  Lectin pathway (MBL):  Mannan binding lectin (AKA: mannose binding protein) binds to surface of the microbe bearing mannan (polymer of mannose)  Binding causes (++) of MASP (MBP-Associated serine proteases) → cleave C2 & C4  Activation of classic pathway  C3a & C5a are anaphylatoxins:  ↑ vascular permeability & dilatation, & bronchospasm (initiate inflammatory process)  cause mast cell to secrete histamine (‫)الجدول باخر صفحة ماكدلكم عنفس المعلومة بحال نسيتو‬  C5a:     chemotactic activates lipoxygenase pathway of AA activates leukocytes increase integrins affinity so increase adhesion  C3b & iC3b are OPSONINS: augemnets phagocytosis to micobes after binding ti its surface  Plasmin and proteolytic enzymes split C3 and C5  Opsonization:  Attachment of C3b on the membrane of the microbe  Macrophage receptors will recognize C3b  endophagocytosis & degrade the microbe (enzymes).  Defects in the Complement System:      Deficiency of C3 → susceptibility to infections. Deficiency of C2 & C4 → susceptibility to SLE. Deficiency of late components → low MAC → Neisseria infections. ↓ inhibitors of C3 & C5 convertase (↓ DAF (CD55): Decay-accelerating Factor) → PNH (hemolytic anemia) ↓C1 inhibitor → angioneurotic edema Page | 2  Morphologic Appearance of Acute Inflammation:  The morphologic hallmarks of acute inflammatory reactions are:  dilation of small BVs  accumulation of leukocytes & fluid in the extravascular tissue.  Special morphologic patterns are often superimposed on them, depending on:  The severity of the reaction.  Its specific cause.  The tissue and site involved.  The importance of recognizing distinct GROSS & MICROSCOPIC patterns of inflammation is that often provide valuable clues about the underlying cause  Types of fluids that are accumulate:  Catarrhal:  Acute inflammation + mucous hypersecretion  Example: common cold.  Serous:  Abundant, watery, protein-poor fluid with low cellular content  Derived from serum, or mesothelial secretions  Skin blisters, viral infection & cavities (peritoneum, pleura, or pericardium).  Fibrinous: More serious!!     Accumulation of thick exudate, rich in fibrin. More severe injury, more permeability, larger molecules (fibrinogen). Resolved by fibrinolysis (Resolution) or thick fibrous tissue (Organization). Acute Pericarditis: fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus.  Suppurative (Purulent):  Pus:    Creamy yellow or blood-stained fluid Consisting of PMN, MO, tissue debris/necrotic cells Example: acute appendicitis.  Abscess: Focal, collection of pus (1° or 2° infections).  Empyema: Collection of pus within a hollow organ.  Most common Pyogenic organisms: staphylococcus Page | 3  Ulcers:      Defect of the surface lining of an organ or tissue Erosion of the surface epithelium with subepithelial inflammation. Mostly GI tract or skin (Sometimes in esophagus) Caused by trauma, toxic injury or vasculopathy. Gastric Ulcer: H.pylori, Chemicals & Stressful conditions  Outcomes of Acute Inflammation:  Resolution: minimal injury (minimal tissue damage), tissue is capable of regeneration.     Clearance of injurious stimuli. Removal of the exudate, fibrin & debris by macrophages & lymphatic drainage. Reversal of the changes in the microvasculature. Replacement of lost cells (regeneration).  Organization (fibrosis/ scarring): Through formation of Granulation tissue.     Substantial tissue destruction or Tissue cannot regenerate or Extensive fibrinous exudates Always Following abscess formation  Progression to chronic inflammation  Follow persistent acute inflammation or start with it.  Depend on extent of inflammation and type of tissue, may proceed to resolution or scarring.  Effects of Acute Inflammation: BENIFICIAL Elimination of injurious stimulus Dilution of toxins & Entry of Ab Drug transport & Fibrin formation Delivery of nutrients & oxygen Stimulation of the immune response HARMFUL Digestion of normal tissues. Swelling. Inappropriate response.  Role of Mediators: Reaction Vasodilation Fever Pain Tissue damage ↑ vascular permeability Chemotaxis, leukocyte recruitment & activation Principal Mediators Histamine, Prostaglandins IL-1, TNF, Prostaglandins Prostaglandins, Bradykinin Lysosomal enzymes of WBC, ROS C3a, C5a, (LT:C4 , D4 , E4), Histamine C3a, C5a, TNF, IL-1, Chemokines, LT B4 ----------------------------------------- Page | 4