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