2. inflammation cellular events dr ashutosh kumar
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Transcript of 2. inflammation cellular events dr ashutosh kumar
summary
Inflammation-acute and chronic
Acute - cardinal sign
stimuli
changes -vascular & cellular
•vascular- vasodilation;
increased vascular permeability
transcytosis
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
STEPS OF EXTRAVASATION OF INFLAMMATORY CELLS
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
LEUCOCYTE ADHESION AND TRANSMIGRATION-MECHASINMS
DUE TO ADHESION MOLECULES
4 CLASSES OF ADHESION MOLECULES Selectins
Immunoglobulin class
Integrins
Mucin like glycoproteins
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
ADHESION MOLECULES
IMMUNOGLOBULIN CLASS
EXPRESSED ON ENDOTHELIAL CELLS
ICAM-1:INTERCELLULAR ADHESION MOLECULE
VCAM-1:VASCULAR CELL ADHESION MOLECULE
ACT AS LIGANDS TO INTEGRINS
ADHESION MOLECULES
INTEGRINS
HETERODIMERIC CELL SURFACE PROTEINS
+ ON MANY CELLS
CELL-CELL AND CELL-MATRIX INTERACTIONS
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
Innflammation induces redistribution of adhesion molecules
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,
Stages of Phagocytosis: Chemotaxis:
DEFINITION- Process Of Directed Cell Migration Along A Chemical Gradient
Responsible for emigration of leucocytes towards the site of injury
CHEMOTAXIS-AGENTS
EXOGENOUS BACTERIAL PRODUCTS-COMMONEST
PEPTIDES OR LIPIDS
ENDOGENOUS COMPLEMENT COMPONENTS-C5a
LEUKOTRIENE B4
CYTOKINES-IL-8
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
It is going that way:
Neutrophil Crawling on a Glass Slide
RECRUITMENT OF LEUCOCYTES TO SITE OF INJURY
INITIAL 6-24 HOURS– NEUTROPHILS
LATER-- MONOCYTES
Recognition of Microbes and Dead Tissues
Phagocytes are Attracted to Site of Infection by Chemotaxis
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.
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.
Process of Phagocytosis
KILLING AND DEGRADATION
O2 DEPENDENT-MORE IMPORTANT
O2 INDEPENDENT
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
O2 DEPENDENT MECHANISMS
Hydrogen peroxide not very effective by itself
Converted by MPO in presence of Cl to form HOCl (hypochlorite)
O2 INDEPENDENT MECHANISMS
Bacterial permeability increasing protein-phospholipase activation
Lysozyme
Lactoferrin
Major basic protein-for parasites
Elastase
DEGRADATION
After killing microbes are degraded in lysosomes by acid hydrolases
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
INFLAMMATION: REGULATION
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
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