INFLAMMATION

Inflammation

n protective vascular connective tissue reaction to injurious stimuli

n Dilute

n Destroy

n Isolate

n Initiate repair

n Acute and chronic forms

Acute inflammation

n Immediate and early response to tissue injury (physical, chemical, microbiologic, etc.)

n Causes of Inflammation

n Physical – can be mechanical (accident injury/assault)  or environmental (severe cold and heat -burns)

n Chemical – for example : Acid ‘burns’, drugs, venom.

n Infection – bacteria, viruses, fungi and other parasites

n Ischemia –

n Immune – autoimmune conditions and allergies.

Vasular events

Vasodilation

n Brief arteriolar vasoconstriction followed by vasodilation

n leads to warmth and redness

n opens microvascular beds

n increased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into interstitium (vascular permeability still not increased yet)

Vascular leakage

n Vascular permeability (leakiness) commences

n Transudate gives way to exudate (protein-rich)

n Increases interstitial osmotic pressure contributing to edema (water and ions)

n Vascular permeability (leakiness) commences

n Transudate gives way to exudate (protein-rich)

n Increases interstitial osmotic pressure contributing to edema (water and ions)

n Five mechanisms known to cause vascular leakiness

n Histamines, bradykinins, leukotrienes cause  early, brief (15 – 30 min.) immediate transient response - endothelial cell contraction of venules (not arterioles, capillaries)

n Cytokine mediators (TNF, IL-1) induce endothelial cell junction retraction (4 – 6 hrs post injury, lasting 24 hrs or more)

n Severe injuries - cause immediate direct endothelial cell damage (necrosis, detachment)

n may cause delayed damage as in thermal, UV injury or bacterial toxins (delayed prolonged leakage)

n leukocytes may damage endothelium through activation and release of toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent endothelial cell injury) making the vessel leaky

n Certain mediators (VEGF) may cause increased transcytosis via intracellular  vesicles which travel from the luminal to basement membrane surface of the endothelial cell

Cellular events

n Leukocytes leave vasculature through following sequence of events:

n Margination and rolling

n Adhesion and transmigration

n Chemotaxis and activation

n then participate in:

n Phagocytosis and degranulation

n Leukocyte-induced tissue injury

Margination and Rolling

n Early rolling adhesion mediated by selectin family:

n E-selectin (endothelium), P-selectin (platelets, endothelium), L-selectin

Adhesion

n Rolling comes to  stop and adhesion results

n Other sets of adhesion molecules participate:

n Endothelial: ICAM-1, VCAM-1

n Leukocyte: LFA-1(Lymphocyte function-associated antigen 1), Mac-1 (Macrophage-1 antigen), VLA-4 (Very Late Antigen-4)

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

Transmigration (diapedesis)

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

n Must then cross basement membrane

n Collagenases

n Integrins

Chemotaxis

n Leukocytes follow chemical gradient to site of injury (chemotaxis)

n Soluble bacterial products

n Complement components (C5a)

n Cytokines (chemokine family e.g., IL-8)

n LTB₄ (AA metabolite)

Chemotaxis and Activation

n Leukocytes:

n  extend pseudopods with overlying surface adhesion molecules (integrins) that bind ECM during chemotaxis

n undergo activation:

n Prepare AA metabolites from phospholipids

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

n Regulate leukocyte adhesion molecule affinity as needed

Phagocytosis and Degranulation

n Once at site of injury, leukocytes:

n Recognize and attach

n Engulf (form phagocytic vacuole)

n Kill (degrade)

Leukocyte granules

n Other antimicrobials in leukocyte granules:

n Bactericidal permeability increasing protein (BPI)

n Lysozyme

n Lactoferrin

n Defensins (punch holes in membranes)

Complement system

nComponents C1-C9 present in inactive form

nActivated via classic (C1) or alternative (C3) pathways to generate MAC (C5 – C9) that punch holes in microbe membranes

nIn acute inflammation

nVasodilation, vascular permeability, mast cell degranulation (C3a, C5a)

nLeukocyte chemotaxin, increases integrin avidity (C5a)

nAs an opsonin, increases phagocytosis (C3b, C3bi)

n

Possible outcomes of acute inflammation

nComplete resolution

nLittle tissue damage

nCapable of regeneration

nScarring (fibrosis)

nIn tissues unable to regenerate

nExcessive fibrin deposition organized into fibrous tissue

nAbscess formation occurs with some bacterial or fungal infections

nProgression to chronic inflammation

Chronic inflammation

nLymphocyte, macrophage, plasma cell (mononuclear cell) infiltration

nTissue destruction by inflammatory cells

nAttempts at repair with fibrosis and angiogenesis (new vessel formation)

nWhen acute phase cannot be resolved

nPersistent injury or infection (ulcer, TB)

nProlonged toxic agent exposure (silica)

nAutoimmune disease states (RA, SLE)

nMacrophages

nScattered all  over (microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc.

nCirculate as monocytes and reach site of injury within 24 – 48 hrs and transform

nBecome activated by T cell-derived cytokines, endotoxins, and other products of inflammation

nEosinophils

nFound especially at sites of parasitic infection, or at allergic (IgE-mediated) sites

Granulomatous Inflammation

nClusters of T cell-activated macrophages, which engulf and surround indigestible foreign bodies (mycobacteria, H. capsulatum, silica, suture material)

nResemble epithelial cells, therefore called “epithelioid” granulomas

Patterns of acute and chronic inflammation

nSerous

nWatery, protein-poor effusion (e.g., blister)

nFibrinous

nFibrin accumulation

nEither entirely removed or becomes fibrotic

nSuppurative

nPresence of pus (pyogenic staph spp.)

nOften walled-off if persistent

nUlceration

nNecrotic and eroded epithelial surface

nUnderlying acute and chronic inflammation

nTrauma, toxins, vascular insufficiency

Systemic effects

nFever

ncytokine-mediated (esp. IL-1, IL-6, TNF) acute-phase reactions including

nAnorexia

nSkeletal muscle protein degradation

nHypotension

nLeukocytosis

nElevated white blood cell count

nBacterial infection (neutrophilia)

nParasitic infection (eosinophilia)

nViral infection (lymphocytosis)