2. inflammation cellular events dr ashutosh kumar
TRANSCRIPT
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summary
Inflammation-acute and chronic
Acute - cardinal sign
stimuli
changes -vascular & cellular
•vascular- vasodilation;
increased vascular permeability
transcytosis
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ACUTE INFLAMMATION-CELLULAR EVENTS
“AIM IS TO DELIVER LEUCOCYTES TO THE SITE OF INJURY”
LUMINAL
MARGINATION ROLLING ADHESION
TRANSMIGRATION ACROSS ENDOTHELIUM
MIGRATION IN INTERSTITIAL TISSUES
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STEPS OF EXTRAVASATION OF INFLAMMATORY CELLS
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ACUTE INFLAMMATION-CELLULAR EVENTS
MARGINATION- Increased No. Of WBCs In The Periphery Adjacent To Endothelium
ROLLING- Slow Tumbling And Transient Adhesion
PAVEMENTING- Complete Lining Of Endothelium By WBCs
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LEUCOCYTE ADHESION AND TRANSMIGRATION-MECHASINMS
DUE TO ADHESION MOLECULES
4 CLASSES OF ADHESION MOLECULES Selectins
Immunoglobulin class
Integrins
Mucin like glycoproteins
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ADHESION MOLECULES
SELECTINS
ADHESION OF LEUCOCYTES TO ENDOTHELIAL CELLS
E-SELECTINS On endothelial cells Bind to CHO groups on granulocytes,monocytes.Memory T cells
P-SELECTINS
Endo And Platelets Bind Neutro,T-Lymphos, monos
L-SELECTINS impt in homing
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ADHESION MOLECULES
IMMUNOGLOBULIN CLASS
EXPRESSED ON ENDOTHELIAL CELLS
ICAM-1:INTERCELLULAR ADHESION MOLECULE
VCAM-1:VASCULAR CELL ADHESION MOLECULE
ACT AS LIGANDS TO INTEGRINS
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ADHESION MOLECULES
INTEGRINS
HETERODIMERIC CELL SURFACE PROTEINS
+ ON MANY CELLS
CELL-CELL AND CELL-MATRIX INTERACTIONS
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ENDOTHELILIAL MOLECULE
LEUKOCYTE MOLECULE ROLE
GLYCAM1 L-selectin ROLLING
P- SELECTIN Sialyl-Lewis X–modified proteins ROLLING
E-SELECTIN Sialyl-Lewis X–modified proteins ROLLING+ ADHESION
V CAM 1 CD11/CD18 (β2) integrins (LFA-1, Mac-1)
ADHESION
I CAM 1 VLA-4 (β1) integrin ADHESION+ TRINSMIGRATION
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Innflammation induces redistribution of adhesion molecules
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leukocyte adhesion deficiency type 1: defective biosynthesis of the β2 chain shared by the LFA-1 and Mac-1 integrins.
Leukocyte adhesion deficiency type 2: d/t absence of sialyl-Lewis X,
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Stages of Phagocytosis: Chemotaxis:
DEFINITION- Process Of Directed Cell Migration Along A Chemical Gradient
Responsible for emigration of leucocytes towards the site of injury
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CHEMOTAXIS-AGENTS
EXOGENOUS BACTERIAL PRODUCTS-COMMONEST
PEPTIDES OR LIPIDS
ENDOGENOUS COMPLEMENT COMPONENTS-C5a
LEUKOTRIENE B4
CYTOKINES-IL-8
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CHEMOTAXIS-MECHANISM
Bind to specific receptors on leucocytes
Effector molecules produced-phospholipase,
tyrosinase etc
Second messengers-finally leading to polymerization
of actin
Leucocyte moves by extending filopodia
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It is going that way:
Neutrophil Crawling on a Glass Slide
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RECRUITMENT OF LEUCOCYTES TO SITE OF INJURY
INITIAL 6-24 HOURS– NEUTROPHILS
LATER-- MONOCYTES
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Recognition of Microbes and Dead Tissues
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Phagocytes are Attracted to Site of Infection by Chemotaxis
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Stages of Phagocytosis: Adherence:
Phagocyte plasma membrane attaches to surface of pathogen or foreign material.
Adherence can be inhibited by capsules (S.
pneumoniae) or M protein (S. pyogenes).
Opsonization: Coating process with opsonins that
facilitates attachment.
Opsonins include antibodies and complement
proteins.
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Stages of Phagocytosis (Cont…)
3. Ingestion: pseudopods formation: lead to engulfment of the microbe
4. Digestion: phagolysosome formation.
Lysosomal enzymes includes:
Lysozyme: Destroys cell wall peptidoglycan
Lipases and Proteases
RNAses and DNAses
After digestion, residual body with undigestable material is discharged.
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Process of Phagocytosis
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KILLING AND DEGRADATION
O2 DEPENDENT-MORE IMPORTANT
O2 INDEPENDENT
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O2 DEPENDENT MECHANISMS
Phagocytosis stimulates burst of oxygen consumption
Production of ROS
Superoxide produced during oxidation of NADPH
Superoxide converted to H2O2
Further reduced to hydroxyl radical
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O2 DEPENDENT MECHANISMS
Hydrogen peroxide not very effective by itself
Converted by MPO in presence of Cl to form HOCl (hypochlorite)
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O2 INDEPENDENT MECHANISMS
Bacterial permeability increasing protein-phospholipase activation
Lysozyme
Lactoferrin
Major basic protein-for parasites
Elastase
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DEGRADATION
After killing microbes are degraded in lysosomes by acid hydrolases
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LEUCOCYTE INDUCED TISSUE INJURY
Protector becoming offender
Release of microbicidal products into EC space
Endothelial injury and tissue necrosis
Amplify inflammation
Eg.-ARDS, acute transplant rejection,
glomerulonephritis
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INFLAMMATION: REGULATION
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DEFECTS IN LEUCOCYTE FUNCTION
GENETIC
ADHESION DEFECTS- LAD1, LAD2
INTEGRINS AND SELECTIN RECEPTORS DEFECTIVE
REC BACTERIAL INFECTIONS AND IMPAIRED HEALING
DEFECTS IN PHAGOLYSOSOME FUNCTION CHEDIAK HIGASHI SYN
AR
DEFECTIVE TRANSFER OF LYSOSOMAL ENZYMES
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DEFECTS IN LEUCOCYTE FUNCTION
DEFECT IN MICROBICIDAL ACTIVITY CGD-DEFECTS IN NADPH OXIDASE REC BACTERIAL INFECTIONS
MPO DEF
ACQUIRED-VARIOUS ASPECTS LIKE PHAGO,CHEMO ETC AFFECTED
DM MALIGNANCY MALNUTRITION ANEMIA