HEAT REDNESS SWELLING PAIN LOSS OF5 Cardinal Signs of Inflammation5 Cardinal Signs of Inflammation
4 cardinal clinical signs of inflammation4 cardinal clinical signs of inflammationdescribed by Celsus, 1 A.D.:described by Celsus, 1 A.D.:• Rubor - redness• Tumor - swelling• Calor - heat• Dolor - pain• Virchow added a fifth--loss offunction(functio laesa)
Steps Of Inflammatory ResponseSteps Of Inflammatory Response• Remembered as five Rs:• (1) Recognition of injurious agent• (2) Recruitment of leukocytes• (3) Removal of agent• (4) Regulation of response• (5) Resolution (repair).
3.Killing and Degradation of Microbes3.Killing and Degradation of Microbes• Important microbicidal substances :reactive oxygen species (ROS) andlysosomal enzymes• ROS• HOCl• (hypochlorous radical)•Superoxide radicals(superoxide,H2O2, and OH•).• Reactive nitrogen species( NO)
CHEMOKINESCHEMOKINES• 2 functions : leukocyte recruitment ininflam. & N anatomic organization of cellsin lymphoid and other tissues• Four groups• Two major groups• CXC :IL-8• CC chemokines:MCP-1 , MIP-1α,RANTES (regulated on activation normalT expressed and secreted) and eotaxin .
Reactive Oxygen Species (ROSReactive Oxygen Species (ROS• Synthesized via NADPH oxidase(phagocyte oxidase) pathway• Action (1) endothelial damage, withthrombosis & ↑ perm.• (2) protease activation andantiprotease inactivation• (3) direct injury to other cells• Catalase, SOD, glutathione -↓ toxicity
NONO• Synthesized from l-arginine, molecularO2, NADPH by enzyme NOS.• 3 isoforms of NOS• Type I (nNOS)• Type II (iNOS) present in macrophages& EC induced by IL-1, TNF,IFN-γ,bacterial endotoxin• Type III (eNOS)
Critical steps : activation of C3Critical steps : activation of C3• (1) Classical pathway : fixation of C1to antig-antib complexes• (2) Alternative pathway: bacterialpolysaccharides / microbial cell-wallcomponents, involve properdin andfactors B , D• (3) Lectin pathway: plasma lectinbinds mannose residues on microbes, activates early component of CP
ComplementComplement• 3 pathways form C3 convertase :cleavesC3 to C3a and C3b• C3b deposits on cell or microbial surface• Binds to C3 convertase complex to formC5 convertase• C5 convertase cleaves C5 → C5a & C5b• Initiate final stages of assembly of C6 toC9• Thrombin : cleave C5
ComplementComplement• 1.Anaphylatoxins: C3a and C5a↑vascular perm. and vasodilation ,inducemast cells to release histamine.• 2.C5a: activates lipoxygenase pathway• 3.Leukocyte activation, adhesion, andchemotaxis. C5a• 4.Phagocytosis: C3b & iC3b act asopsonins• 5.Lysis of microbes - MAC
Coagulation and Kinin SystemsCoagulation and Kinin Systems• 4 systems activated by Hagemanfactor (factor XIIa)• (1) Kinin system• (2) Clotting system• (3) Fibrinolytic system• 4) Complement system.
Coagulation and Kinin SystemsCoagulation and Kinin Systems
Role of Mediators in DifferentRole of Mediators in DifferentReactions of InflammationReactions of Inflammation• 1.Vasodilation:Prostaglandins, Nitric oxide Histamine• 2.↑ vascular perm:Histamine and serotoninC3a and C5aBradykininLeukotrienes C4, D4, E4PAFSubstance P
Mediators in InflammationMediators in Inflammation• 3. Leukocyte recruitment andactivationTNF, IL-1ChemokinesC3a, C5aLeukotriene B4Bacterial products, e.g., N-formylmethyl peptides
MACROPHAGESMACROPHAGESFUNCTION–Filters: particulate matter,microbes,senescent cells–Alert T and B lymphocytes toinjurious stimuli• Lymphocytes, Plasma Cells,Eosinophils, and Mast Cells
Settings For Chronic InflammationSettings For Chronic Inflammation• 1.Microbes difficult to eradicateMycobacteria, Treponema pallidum ,viruses and fungi• 2.Immune-mediated inflammatorydiseases : RA ,IBD, Asthma• 3.Toxic agents :Silica, atherosclerosis
GRANULOMATOUS INFLAMMATIONGRANULOMATOUS INFLAMMATION• Distinctive pattern of chronicinflammation• Characterized by aggregates ofactivated macrophages that assumean epithelioid appearance
Diseases with GranulomatousDiseases with GranulomatousInflammationInflammation• Tuberculosis :M. tuberculosis• Noncaseating tubercle : a focus ofepithelioid cells, rimmed by fibroblasts,lymphocytes, histiocytes, occasionalgiant cells• Caseating tubercle: central amorphousgranular debris, loss of all cellular detail;acid-fast bacilli
2.Acute-phase proteins2.Acute-phase proteins• 2.Synthesized in liver• Up-regulated by IL-6• I) CRP II) Fibrinogen III)Serum amyloid A(SAA) protein.• Fibrinogen cause rouleaux- ↑ ESR• CRP: ↑ risk of MI or stroke in pts. withatherosclerotic vascular disease
3. Leukocytosis• TNF & IL-1-release cells from BM .Shift to left• CSFs - ↑ output of leukocytes from BM• Neutrophilia , lymphocytosis ,eosinophilia , leukopenia
Other manifestationsOther manifestations• ↑ heart rate and BP• ↓ sweating• Rigors (shivering)• Chills• Anorexia, somnolence & malaise:cytokines on brain cells• Chronic inflammation: wasting syndromecalled cachexia, TNF- mediated appetitesuppression & mobilization of fat stores
SEPTIC SHOCKSEPTIC SHOCK• High levels of TNF cause DIC,hypoglycemia, and hypotensiveshock.
1.A 65-year-old woman had fever the past day.On physical examination her temperature is 39 Cand blood pressure 90/50 mm Hg with heart rateof 106/minute. A blood culture is positive forEscherichia coli. Her central line pressure fallsmarkedly. She goes into hypovolemic shock as aresult of the widespread inappropriate release of achemical mediator derived from macrophages.Which of the following mediators is most likely toproduce these findings?A Nitric oxideB BradykininC HistamineD ProstacyclinE Complement C3a
2.The major difference between atransudate and an exudate is(A) transudate has proteins whereasexudate is essentially devoid of proteins(B) both these are only seen during acuteinflammatory processes(C) both are associated with a Suppurativeor Purulent inflammatory process(D) transudate is associated with serousinflammation whereas exudate isassociated with fibrinous inflammation
3.Granulomatous Inflammation isassociated with which of the followinga. distinct acute inflammatoryprocessb. distinct chronic inflammatoryprocessc. persistent B-cell response tocertain microbesd. IgM mediated response
4.Which of the following is/are consideredan anaphylatoxins(s)(A) lipoxins(B) leukotrines(C) C3a(D) IL-1 and TNF
5.What is the most common form ofincreased vascular permeabilityassociated with acute inflammation(A) direct endothelial injury(B) endothelial cell retraction(C) endothelial cell contraction(D) leukocyte-dependent endothelialdamage
6.Endothelial cell contraction &retraction occur ina) Postcapillary venulesb) Capillariesc) Arteriolesd) All of the above