Acute inflammation 3

By Dr. S. Homathy

• This is augmented by slowing of the blood flow and increased vascular permeability,

• fluid leaves the vessel causing– leukocytes to settle-out of the central flow column – and “marginate” along the endothelial surface

• Leucocytes accumulate at the periphery of vessels–Margination

• Normal flow

• stasis

Rolling

• Endothelial cells and leukocytes have complementary surface adhesion molecules

• which briefly stick and release causing the leukocyte to roll along the endothelium– like a tumbleweed until – it eventually comes to a stop as mutual adhesion

reaches a peak

Rolling

• Then WBC tumble on the endothelial surface– Transiently sticking along the way- rolling

• Lose and transient adhesions are mediated by the selectin family of molecules

• Selectins are receptor expressed on leukocytes and endothelium– They bind to the selectin sugars

E-selectin - endotheliumP-selectin - endothelium and PlateletsL-selectin - leukocytes

• They are expressed at low level / absent on normal cells

• They are up- regulated after stimulation by specific mediaters.

• upregulated on endothelium by cytokines (TNF, IL-1) at injury sites

Adhesion

• Rolling comes to a stop and adhesion results before leukocytes crawling between endothelial cells

• The firm adhesionis mediated by molecules of immunoglobulin superfamily

• The molecules participate are:

– Endothelial: ICAM-1, VCAM-1

– Leukocyte: LFA-1, Mac-1, VLA-4(ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4)

• Ordinarily down-regulated or in an inactive conformation, but inflammation alters this

• Cytokines –TNF and IL-1induce the expression of both ICAM-1 and VCAM-1

Leukocyte adhesion

Transmigration (Diapedesis)

• Occurs after firm adhesion within the systemic venules and pulmonary capillaries via PECAM –1 (CD31)

• Must then cross basement membrane

• Leukocytes cross the BM by focally degrading them with secreted – Collagenases– Integrins

• Early in inflammatory response mostly PMNs,

• but as cytokine and chemotactic signals change with progression of inflammatory response,

• alteration of endothelial cell adhesion molecule expression – activates other populations of leukocytes to adhere

(monocytes, lymphocytes, etc)

• In most acute inflammatory lesions PNL predominate in the first 6-24 hrs

• Then replaced by monocytes in 24-48 hrs

• Neutrophils undergo apoptosis within 24-48 hrs of exiting the blood stream

Leukocyte emigration (TRANSMIGRATION)

Chemotaxis and Activation• Leukocytes follow chemical gradient to site of injury

(chemotaxis)• It is the unidirectional migration of cells towards an

attractant– Soluble bacterial products– Complement components (C5a)– Cytokines (chemokine family e.g., IL-8)– LTB4 (AA metabolite)

• Chemotactic agents bind surface receptors

• inducing calcium mobilization and assembly of cytoskeletal contractile elements

Leukocytes:• extend pseudopods with overlying surface

adhesion molecules (integrins) that bind ECM during chemotaxis

• undergo activation:– Prepare AA metabolites from phospholipids• Prostaglandin (and thromboxanes)• Leukotrienes• Lipoxins

• Prepare for degranulation and release of lysosomal enzymes (oxidative burst)

• Regulate leukocyte adhesion molecule affinity as needed

Chemotaxis

Phagocytosis and Degranulation

• Once at site of injury, leukocytes involve several steps:– Recognize and attach– Engulf (form phagocytic vacuole)– Kill (degrade)

Recognition and Binding

• Recognition and attachment of leukocytes is facilitated by serum protein- opsonins

• Opsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG)

• Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding

Phagocytosis - Attachment