1、Lecture 5BIOL 5331Constitutive Defenses of the HostBIOL 533Lecture 5Medical MicrobiologyLecture 5BIOL 5332Constitutive Defenses Barriers to entry See Schaechter text,Table 6.1 Mucous membranescovered by protective layer of mucus Mechanical and chemical barrier that allows proper functioning Cross-li
2、nked gel structure composed of glycoprotein subunitsLecture 5BIOL 5333Mucus Membranes Entraps particles and prevents them from getting to mucus membrane Hydrophilic:allows passage of a number of bodily substances Antimicrobial substances(lysozyme and peroxidase)Can withstand substantial weight,but s
3、till be propelled by ciliaLecture 5BIOL 5334Defenses of Deep Tissues Role of constitutive defenses List of humoral mediators of constitutive defenses(See Schaechter text,Table 6.2)Lecture 5BIOL 5335Defenses of Deep Tissues Role of constitutive defenses,contd.Inflammatory response does not require pr
4、evious contact with microorganism Elicited by complex effectors,many of which are complement system Normally at basal level and must be further increased by presence of microorganisms in tissues Most important consequence of activity is phagocyte attractionLecture 5BIOL 5336Defenses of Deep Tissues
5、Interaction of constitutive(inflammatory response)and inducible defenses(immune response)Inducible response cannot occur without constitutive mediators Mediators lead to induction of immune response and also defend against microbial invaderLecture 5BIOL 5337Inflammation General aspects Reaction to t
6、issue injurymanifested by pain,swelling,heat,and throbbing of location Location appears red and shiny,hot and painful to touch as a result of changes in local blood vessels and lymphatics Tissues may return to normal or scarring may resultLecture 5BIOL 5338Inflammation Tissues may return to normal o
7、r scarring may result;depends on extent of damage done:By injury By infecting microbes By inflammatory responseLecture 5BIOL 5339Inflammation Description of changes Blood supply increases to affected part due to vasodilation Capillaries become more permeable,allowing fluid and large molecules to mov
8、e into tissues Consequence of inflammation pH of inflamed tissues lowered Production of lactic acidantimicrobialLecture 5BIOL 53310Inflammation Molecular basis of inflammatory response and acute phase response Inflammatory response starts with activation of complement or of blood-clotting cascade Co
9、mplement and clotting are interactive Either can set off the other Normally,clotting is seen when acute inflammatory response is severeLecture 5BIOL 53311Molecular Basis Inflammatory response leads to production and release of a number of chemical effectors of inflammation responsible for vascular p
10、ermeability,vasodilation,and pain Histamine Kinin Leukotrienes and prostaglandinsLecture 5BIOL 53312Molecular Basis Histamine is one of best-known Dilates blood vessels and increases permeability Mechanism of production Three peptides(C3a,C4a,and C5a;anaphylotoxins)produced by activation of compleme
11、nt system Stimulate release of histamine from mast cellsLecture 5BIOL 53313Molecular Basis Kininsmall basic peptides Alter vascular tone Increase permeability May initiate or potentiate release of other chemical mediators from leukocytes Bradykinin is best-knownLecture 5BIOL 53314Molecular Basis Pro
12、duction of kininsHageman factor activated during inflammation(one of substances that can activate is LPS)Induces production of kinins Also plays important role in blood coagulation Cleavage of precursor kininogens activated by enzymes(kallikreins)produced during clotting cascade or release from gran
13、ulocytesLecture 5BIOL 53315Molecular Basis Leukotrienes and prostaglandins Act on motility and metabolism of wbc Two plus certain phospholipids cause aggregation of blood platelets(important to stop bleeding)Prostaglandins synthesized in hypothalamus act on temperature regulatory centers of brain an
14、d cause feverLecture 5BIOL 53316Molecular Basis Aspirin prevents both synthesis and effects of prostaglandins Fever provides:Important warning sign of infection Interference with antimicrobial mechanismLecture 5BIOL 53317Mechanism of Inflammation Injured tissue cells release inflammatory mediators t
15、hat activate inner lining(endothelium)of capillariesLecture 5BIOL 53318Mechanism of Inflammation Within capillaries,selectins(cell adhesion molecules)Psel then Esel Randomly attract and attach neutrophils Slow them down;cause to move through capillariesLecture 5BIOL 53319Mechanism of Inflammation En
16、counter inflammatory activators Integrins on neutrophils(adhesion receptors)Attach to endothelial receptors ICAM1intracellular cell adhesion molecule VCAMvascular adhesion moleculeLecture 5BIOL 53320Mechanism of Inflammation Neutrophils stick to endothelium and stop moving Undergo dramatic shape cha
17、nges;migrate through wall into tissue spaceLecture 5BIOL 53321Mechanism of Inflammation Inflammatory mediators released by injured tissue also raise acidity in extracellular fluid Decrease in pH activates extracellular enzyme kallikrein;splits bradykin from precursorLecture 5BIOL 53322Mechanism of I
18、nflammation Bradykin binds to receptors on capillary wall,opening junctions between cells;allows leukocytes and fluid into tissues Also,simultaneously binds to mast cells in connective tissue Activates mast cells(by influx Ca+2)degranulation;release of preformed mediators histamineLecture 5BIOL 5332
19、3Mechanism of Inflammation If nerves damaged,they release substance P;also bind to mast cells,increasing preformed mediator release Histamine makes intercellular junctions in capillary wall wider,so more fluid,leukocytes,kallikrein,and bradykinin precursors move out,causing edemaLecture 5BIOL 53324M
20、echanism of Inflammation Bradykinin then binds to nearby capillary cells and stimulates production of prostaglandins PGE2 and PGE2,causing tissue swelling Prostaglandins also bind to nerve endings,causing painLecture 5BIOL 53325Mechanism of Inflammation Change in mast cell plasma membrane permeabili
21、ty allows phospholipase A2 to be converted to arachidonic acid Arachidonic acid proceeds through cyclo-oxygenase pathway-OR-lipoxygenase pathway(depends on mast cell type)Lecture 5BIOL 53326Mechanism of Inflammation Pathways yield synthesized mediators Prostaglandin E2 F2 Thromboxane A2 Slow-reactin
22、g substance Leukotrienes See Prescott,Fig.29.13 Biochemical Effects of InflammationLecture 5BIOL 53327Inflammation Acute phase responseduring inflammation,certain proteins are released(chiefly from the liver)and their concentration rises in seraLecture 5BIOL 53328Acute Phase Response Rise in sera is
23、 disproportionate C-reactive protein(reacts with C polysaccharide of pneumococci and other bacterial Ag)and serum amyloid A protein increase 1000 times or more1-antitrypsin and complement factor B increase by 2 or 3 foldLecture 5BIOL 53329Acute Phase Response Different functions C-reactive proteinen
24、hances inflammatory response by activating complement1-antitrypsininhibits proteases that function in inflammationLecture 5BIOL 53330Acute Phase Response Other important proteins released Those that avidly bind iron and other metals Reduces availability of required ions for microorganisms Helps inhi
25、bit microbe growth Induction of responseproteins(cytokines)formed by“activated monocytes”Lecture 5BIOL 53331Induction of Response Interleukin-1(IL-1);endogenous pyrogen Causes fever by stimulating prostaglandins Stimulates proliferation of cells involved in immune response Enhances stickiness of ins
26、ide surface of endothelial cells in capillaries to neutrophils Facilitate movement to particular areaLecture 5BIOL 53332Induction of Response Tumor necrosis factor(TNF;cachectin)Has antitumor activity Causes weight loss(severe problem in certain chronic infections,such as tuberculosis and some cance
27、rs)Lecture 5BIOL 53333Induction of Response Characteristics of both IL-1 and TNF Play major role in“shock response”elicited during some serious bacterial infections Both made in response to presence of microorganismsLecture 5BIOL 53334Induction of Response Other important cytokines Interleukin-2 Inv
28、olved in proliferation of immunologically important cells Used therapeutically to treat certain tumors Interleukin-6(hepatocyte-stimulating factor)Involved in synthesis of acute phase response proteins by the liverLecture 5BIOL 53335Complement General characteristics Comprises as many as 26 proteins
29、 found in sera and some as a part of cell membranes Mediates large number of biological effects Interacts with other complex systems,including Blood-clotting Specific immune responseLecture 5BIOL 53336Complement Normally present at basal level When activated,enhances antimicrobial defenses Making in
30、truding bacteria susceptible to phagocytosis Causing lysis of bacteria Producing chemotactic substances Promoting inflammatory responseLecture 5BIOL 53337Complement Activation(proteolytic cleavage of precursor)in one of two ways that produce same end products Classical pathway:activated by presence
31、of Ag-Ab complexes Alternative pathway:independent of Ab elicited by bacterial surface components,such as LPSLecture 5BIOL 53338Role of Complement In patient studies,patients genetically lacking some of complement components are very susceptible to bacterial diseases(some life-threatening)Enhancing
32、phagocytosis Recruitment of wbc by chemotactic protein Facilitation by proteins called opsoninsLecture 5BIOL 53339Role of Complement Responsible for lysis of:Bacteria Some viruses Foreign cells Can even lyse foreign cells with membranes containing viral proteinLecture 5BIOL 53340Role of Complement M
33、echanism of lysiscarried out by membrane attack complex Inserts itself into membranes and alters their permeability Particularly important with bacteria that have resistance mechanisms against phagocytosisNeisseria(gonorrhea)&streptococci(meningitis)Patients with genetic deficiencies for mak compone
34、nts very susceptible to these diseasesLecture 5BIOL 53341Role of Complement Induces inflammatory response via formation of interleukin-1,TNF,and anaphylatoxins Beneficial:inflammatory response helps fight invading microbesLecture 5BIOL 53342Role of Complement Negative:in patients with hypersensitivity disorders,inflammatory response damages sensitive tissue Cause leukocytes to secrete lysosomal enzymes Diseases include rheumatoid arthritis,serum sickness,and infective endocarditisLecture 5BIOL 53343Lecture 5 Questions?Comments?Assignments.
