Transcript Acute inflammation - V4US-33rd

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 - endothelium
P-selectin - endothelium and Platelets
L-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