Acute Inflammation PDF 2015-2014

Acute Inflammation Department of Pathology and Forensic Medicine College of Medicine University of Kufa 2015 _ 2014 Chemical mediators of acute inflammation Proteases (plasma proteins, produced in-1.liver).A- Kinins (Bradykinin and Kallikrein).B-Comple...

Acute Inflammation Department of Pathology and Forensic Medicine College of Medicine University of Kufa 2015 _ 2014 Chemical mediators of acute inflammation Proteases (plasma proteins, produced in-1.liver).A- Kinins (Bradykinin and Kallikrein).B-Complement system C3a, C5a. C- Coagulation / fibrinolytic system.Prostaglandins / Leukotrienes -2.Metabolites of arachidonic acid Synthesis blocked by NSAIDs, e.g. aspirin Cytokines / chemokines (produced by -3.wbc’s) !Many and varied ,Interleukins, PAF, TNF alpha, PDGF....TGF beta  :Other inflammatory mediators From platelets: 5-HT, Histamine, ADP-1.From neutrophils: Lysosomal constituents-2 (Products released on neutrophil death).From endothelium: Prostacyclin,Nitric oxide-3 Plasminogen activators / inhibitors-4. : Oxygen derived free radicals-5 a- Endothelial damage b- inactivation of antiproteases c- injury to other cells  Vascular changes CHEMICAL MEDIATORS Three phases: Phase I:Immediate early response (1/2 hr) A- HISTAMINE: Released from mast cells, basophils and -.platelets - In response to many stimuli: physical damage, immunologic reactions, C3a, C5a, IL1, factors.from neutrophils and platelets.vascular dilatation transient increase in vascular.permeability.pain. Not chemotactic Phase II : ( Immediate sustained response).Not always seen Due to direct damage to endothelial cells Phase III Delayed response (Peaks about 3 hrs) ,Many and varied chemical mediators -1.interlinked and of varying importance Incompletely understood -2 e.g. leukotrienes, bradykinin IMPORTANT because of possibility of.therapeutic intervention  Know a few mediators for each major step in the inflammatory process :Vascular dilatation -1.Histamine, prostaglandins, nitric oxide :Increase in vascular permeability -2.Transient – Histamine.Bradykinin, leukotrienes C4, D4, E4 Emigration of neutrophils: (chemotactant -3 factors) C5a, leukotriene B4, bacterial products ((Lipopolysaccharide  Mechanisms of vascular leakage Endothelial contraction -->gaps -1 histamine, leukotrienes ---. Cytoskeletal reorganisation --> gaps -2. Cytokines IL-1 and TNF, hypoxia -- Direct injury -toxic burns, chemicals -3 :Leukocyte dependent injury -4 toxic oxygen species and enzymes from.leucocytes (pulmonary and glomerular capillaries) Increased transcytosis -channels across endothelial -5.cytoplasm (VEGFA)vascular endothelial growth factor Mechanisms of neutrophil migration Neutrophil adhesion and emigration due to -1 binding of complementary adhesion molecules. on endothelial and neutrophil surfaces Chemical mediators change surface expression -2 :or avidity of adhesion molecules.a- Selectins.b- Immunoglobulins.c- Integrins  How do neutrophils escape from ?vessels Relaxation of inter-endothelial cell-1.junctions Digestion of vascular basement -2.membrane.Movement -3  How do neutrophils move? Diapedesis and Emigration;.Chemotaxis Chemotaxis =movement along concentration.gradients of chemoattractants Receptor-ligand binding-1 Rearrangement of cytoskeleton-2 Production of pseudopod-3  What do neutrophils do? Phagocytosis.Contact, Recognition, Internalisation -1 Cytoskeletal changes(as with chemotaxis)-2  What do neutrophils do? Microbial killing Recognition is facilitated by opsonins-1 e.g. Fc and C3b receptors on phagocyte will recognise organisms coated with.immuno-globulin or complement Phagosomes fuse with lysosomes to -2.produce secondary lysosomes  Killing mechanisms :O2 dependent -1 produces superoxide and hydrogen -.peroxide H2O2 -Myeloperoxidase-halide system --.-produces HOCl Myeloperoxidase independent killing is -–.less efficient :O2 independent-2 Lysozyme & hydrolases - Bactericidal Permeability Increasing -.Protein (BPI).Cationic proteins (‘Defensins’) - Major Basic Protein (MBP; Eosinophils) -  Consequences of Acute Inflammation Local (rubor, calor, dolor, tumor) -1 and Systemic -2  Local complications of acute inflammation :Swelling -1 Blockage of tubes, e.g. bile duct, intestine – :Exudate -2 Compression e.g. cardiac tamponade.Serositis Loss of fluid e.g. burns -3 Pain & loss of function especially if -4.prolonged  Systemic Effects of Acute Inflammation Fever -1.Endogenous pyrogens’ produced: IL1 and TNF -.Prostaglandins, aspirin etc reduce fever - Leukocytosis -2 IL1 and TNF produce an accelerated release from–.marrow Macrophages, T lymphocytes produce colony-stimulating–.factors.Bacterial infections - neutrophils, viral - lymphocytes –.Clinically useful –  Systemic Effects of Acute Inflammation Acute phase response -1 Decreased appetite, altered sleep patterns and :changes in plasma concentrations of :Acute phase proteins.C-reactive protein (CRP) (Clinically useful) antitrypsin 1..Haptoglobin.Fibrinogen.Serum amyloid A protein Acute phase response Spread of micro-organisms and toxins SHOCK a clinical syndrome ACUTE INFLAMMATION: sequelae What may happen after the development ?of acute inflammation.Complete resolution -1 Continued acute inflammation with chronic -2.inflammation; chronic suppuration ,Chronic inflammation and fibrous repair -3.probably with tissue regeneration.Death -4  Resolution :Morphology Changes gradually reverse - :Vascular changes stop -.neutrophils no longer marginate -1.vessel permeability returns to normal -2.vessel calibre returns to normal -3 :Therefore.Exudate drains to lymphatics– Fibrin is degraded by plasmin and other– proteases Neutrophils die, break up and are carried– away or are phagocytosed Damaged tissue might be able to–.regenerate Note that if tissue architecture has been -.destroyed, complete resolution is not possible  Mechanisms of Resolution.All mediators of acute inflammation have short half-lives - May be inactivated by degradation, e.g. heparinase - Inhibitors may bind, e.g. various anti-proteases - May be unstable e.g. some arachidonic acid -.derivatives May be diluted in the exudate, e.g. fibrin -.degradation products Specific inhibitors of acute inflammatory changes -...e.g. lipoxins, endothelin–  Morphological pattern of acute inflammation.serous inflammation _ outpouring of fluid _1 fibrinous inflammation _ sever destructiin _2. either resolution or organization suppurative purulent inflammation abd abscess _3. formation ulceration _4  Morphological pattern of acute inflammation.serous inflammation _ outpouring of fluid _1 fibrinous inflammation _ sever destructiin _2. either resolution or organization suppurative purulent inflammation abd abscess _3. formation ulceration _4  Clinical Examples :LOBAR PNEUMONIA :Causative organism Streptococcus pneumoniae (‘Pneumococcus’) :Population at risk ,Young adults in confined conditions.alcoholics :Clinical course Worsening fever, prostration, hypoxaemia over a.few days.Dry cough.Fairly sudden improvement (‘resolution by crisis’) when.antibodies appear  Skin blister Causes: heat, sunlight, chemical :Predominant features PAIN -1 EXUDATE -2 Collection of fluid strips off overlying epithelium–.more pain, more tissue damage– :Inflammatory cells relatively few– therefore exudate clear UNLESS bacterial infection.develops  Abscess Solid tissues Inflammatory exudate forces tissue apart- Liquefactive necrosis in centre- May cause high pressure therefore PAIN - May cause tissue damage - May squash adjacent structures -  Acute inflammation in serous cavities Exudate pours into cavity ascites, pleural or pericardial effusion - respiratory or cardiac impairment - Localised fibrin deposition - bread and butter’ pericarditis -‘ Disorders of Acute Inflammation.These are rare diseases :for examples Hereditary angio-oedema („angioneurotic (‟oedema.Alpha-1 antitrypsin deficiency.Inherited complement deficiencies.Defects in neutrophil function.Defects in neutrophil numbers  Summary.Transient vasoconstriction of arterioles (few secs)-1.VASODILATATION of arterioles and then capillaries-2 INCREASED PERMEABILITY of blood vessels-3. exudation of protein -rich fluid into tissues slowing of circulation STASIS-4 MARGINATION -5. Chemical ROLLING-6. Mediators.ADHESION-7.EMIGRATION-8 CHEMOTAXIS -9.. PHAGOCYTOSIS- 10 Damage to host tissue, local and systemic effects -11..Sequelae -resolution etc -12