Acute & Chronic Inflammation

Acute & Chronic inflammation • Defn- response of a vascularised living tissue to an irritant. This can be – • 1) living eg. Bacteria,fungi,viruses,parasite • 2) non-living eg. Physical (heat, cold); chemical(acids, alkalis)agent,radiatn,trauma • Classified according to the• A) duration-acute or chronic • B) nature of exudates- fibrinous,serofibrinous or purulent • C) Aetiology- bacterial , viral or fungal

Contd… • Advantages – dilution of irritant • - destruction of injurious agent • Disadv – excessive tissue destruction • -survival of org within macrophages • -hypersensitivity reactions • -repair by fibrosis may lead to disfiguring scars of fibrous bands that cause obs or limit the mobility of joints

Contd… • Acute inflammation (AI) – of short duration & its main characteristics are• Exudatn of fluid& plasma proteins-oedema • Emigratn of leucocytes-mainly neutrophils • Chronic inflammation(CI) – longer duration • Presence of lymphocytes & macrophages • Proliferatn of bld vessels,fibrosis & tissue necrosis. • Celsus – a roman writer listed 4 cardinal signs of inflammation• Rubor, Tumor, Calor & Dolor (redness,swelling, heat & pain). Later a 5 th cardinal sign was added by Virchow • Functio laesa – loss of function

Acute inflammation • 3 major components• 1) vascular changes- changes in vascular flow & caliber - increased vascular permeability • 2) structural changes in microvasculature that permit the plasma proteins & leucocytes to leave the circulation • 3) emigration of the leucocytes from the microcirculation & their accumulation in focus of injury

Vascular changes-within minutes • After inconstant & transient vasoconstrictn of arterioles, lasting for a few seconds, vasodilatation occurs. • It first involves the arterioles & then results in opening of new capillary beds – increased blood flow- cause of heat & redness. • Increased permeability of the micro- vasculature – causes slowing of circulation-outpouring of protein rich fluid into extravascular tissues. • Loss of fluid –concentratn of red cells in small vessels & increased viscosity of blood- stasis. • Peripheral orientation of leucocytes mainly neutrophils along vascular endothelium- leucocyte margination.

Increased vascular permeability (vascular leakage) • Increased vascular permeability- escape of protein rich fluid (exudate) into interstitium is the hallmark of AI. • Loss of protein from plasma- reduces the intravascular osmotic pressure & increases the osmotic pressure of interstitial fluid. • This together with the increased hydrostatic pressure(due to vasodilatation) – marked outflow of fluid & its accumulation in the interstitial tissue which is called edema. • But normal fluid exchange µcirculation are critically dependent on the intactness of vascular endothelium. How does the endo. become leaky?

Mechanisms of vascular leakage • Formation of endothelial gaps in venules- reversible & short lived(15 – 30 min)- elicited by chemical mediators like bradyk. • Cytoskeletal reorganisation (endothelial retraction)- reversible induced by cytokines like interleukin-1,tumor necrosis factor • Direct endo injury –endo necrosis & detach-ment- by toxins, burns, chemicals. • Leukocyte dependent injuy-release toxic O2 species& proteolytic enzymes • Leakage from new bld vessels- as formed during repairangiogenesisdue to VEGF • Increased transcytosis across endo cytoplasm thru’ interconnected vesicles

Cellular events: leucocyte extravasation & phagocytosis • Sequence of events in the journey of leucocytes from lumen to the interstitial tissue, called extravasation is divided into• In lumen: margination , rolling & adhesion (pavementing ). • Transmigration across the endothelium (diapedesis) • Migration in interstitial tissues towards a chemotactic stimulus (chemotaxis)

• In AI- neutrophils predominate in the inflammatory infiltrate during the first 6 – 24 hrs, then replaced by monocytes in 24 – 48 hrs.

Chemotaxis • Defined as locomotion oriented along a chemical gradient. • Chemoattractants-Exogenous–bact products Endogenous- 1) components of complement sys , particularly C5a; 2) products of lipooxygenase pathway leukotrieneB4 ; 3) cytokines eg.IL-8 • Binding of chemotactic agents to sp receptors on leucocyte cell memb.causes increase in I/C Ca+2 through activation of phospholipase C. • This triggers the assembly of contractile elements – actin & myosin responsible for cell movement and the leucocyte moves by extending a pseudopod that pulls the remainder of the cell in the direction of extension.

Phagocytosis • 3 steps• 1) Recognition & attachment of particle to be ingested by the leucocyte which is done by specific substances called opsonins. • Opsonisation of particles such as bacteria enhances the efficiency of phagocytosis • Major opsonoins are-1) Fc fragment of immunoglobulin G(IgG) ; 2) C3b opsonic fragment of C3 – by activatn of immune or non-immune mech. ; 3)collectinscarbohydrate binding proteins of plasma which bind to microbial cell walls. • Corresponding receptors on leucocytes are FcyR which recognise Fc fragment of IgG.

Contd… • Binding of opsonised particle to FcyR causes engulfment, which is enhanced by the complement receptors. • But there should be simultaneous binding to certain cytokines & extracellular fibronectin • With engulfment , there is formation of phagolysosome created by cytoplasmic memb of the cell. • 3) killing /degradation of the ingested material which is largely done by O2 dependent mech. • These release hydrogen peroxide within lysosome • Which is converted to HOCL by the enzyme myeloperoxidase present in azurophilic granules of neutrophil.

Chemical mediators

• • • • • • • • •

Mediators originate from – Plasma or Cells Cellular –a) preformed mediators in secretory granules : histamine – from mast cells,basophils,plts. Serotonin – from platelets lysosomal enzymes – neutrophils & macrophages. b) Newly synthesized – prostaglandins- all leuco.+ platelets + EC. - leukotrienes- all leucocytes - platelet activating factors-all leuco +EC -activated O2 species –all leuco -nitric oxide- macrophages -cytokines-lymphocytes,macrophages,EC

Contd… • Plasma• Factor 12(hageman fac )activation- kinin system(bradykinin) & coagulation / fibrinolysis sys • Complement activation – C3a &C5a – anaphylotoxins - C3b&C5b-9membrane attack complex

Vasoactive amines • Histamine –mast cell granules & released in response to –physical injury,immune reactions,fragments of complement called anaphylotoxins,neuropeptides &cytokines • Serotonin (5-HT)- released from platelets when they aggregate after contact with collagen , thrombin, ADP & Ag-Ab complexes ,

Plasma proteases • Complement system- C3a,C5a-increase vascular permeability & cause vasodilatn by releasing histamine from mast cells. C5a also activates lipoxygenase pathway of AA metabolism in neut & monocytes. • leukocyte adhesion ,chemotaxis& activatn-by C5a • Phagocytosis- C3b &C3bi act as opsonins • Kinin sys- generates bradykin which causesincreased vasular permeability,contractn of smooth muscle, dilatn of bld vessels & pain when injected in skin. factor –10a• Clotting sys- thrombin ,fibrinopeptides & increased vascular permeability, chemotaxis & leucocyte exudation

Arachidonic acid metabolites • Lipoxygenase pathway- leucotriene C4 - LTD4& LTE4- cause VC, bronchospasm & increased permeability • Cycloxygenase pathway-PGI2-VD,inhibits plt agg whereasThromboxane A2VC , promotes plt agg • PGD2,PGE2,PGF2alpha- VD &potentiate oedema • Cytokines – proteins that modulate function of other cell types- prod by act lymph,macrophages, EC,epi & connective tissue cells eg IL-2,IL4,5,10,12,TNF-alpha &beta,IFN-alpha&beta etc. • Chemokinesproteins that act primarily as activators & chemoattractants for specific types of leucocytes eg. IL-8 ,MIP-1alpha(macrophage inflam protein) etc.

Outcomes of AI • Complete resolution • Abscess formation – infections with pyogenic organisms • Healing by connective tissue replacement (fibrosis)- organisation • Progression to chronic inflammation due to - persistent infection - persistent toxins - autoimmune diseases

Chronic inflammation • Inflammatn of prolonged duratn(wks or mon) in which active inflammatn, tissue destructn & attempts at repair are proceeding simultaneously. • Eg. Rheumatoid arthritis, atherosclerosis, tuberculosis & chronic lung diseases etc. • Ch by- infiltratn with mononuclear cells- macrophages, lymphocytes & plasma cells • -tissue destruction by inflammatory cells • - attempts at healing by connective tissue replacement of damaged tissue, by proliferation of small bld vessels (angiogenesis) & fibrosis.

Mononuclear infiltration

• The mononuclear phagocytic sys consistsof closely related cells of bone marrow origin- blood monocytes & tissue macrophages . • The latter are diffusely scattered in connective tissue or clustered in organs such as-liver (kupfer cells) ; spleen & lymph nodes(sinus histiocytes) ; lungs(alveolar macrophages) • All arise from a common precursor in bone marrow, give rise to blood monocytes & from bld these migrate into various tissues & transform into macrophages. • When macrophages are activated by certain cytokines secreted by sensitised T- cells which results in greater ability to phagocytose & kill ingested microbes.

Granulomatous inflammation

• Distinctive pattern of chronic inflammatory reactn in which predominant cell type is an activated macrophage with a modified epithelial- like (epithelioid) appearance. • Granulomas are classified as• Infective-Tb,leprosy,syphilis, actinomycosis • Non-infective- foreign body type • Hypersensitivity- Rheumatic fever • Unknown cause – sarcoidosis. • A granuloma is a focal area of granulomatous inflammation – microscopic aggregation of epithelioid cells surrounded by a collar of mononucloear leukocytes mainly lymphocytes & occ plasma cells.

Morphologic patterns in AI & CI • Serous - outpouring of thin fluid derived from- blood serum or secretions of mesothelial cells lining peritoneal, pleural & pericardial cavities (called effusion).eg skin blister from a burn. • Fibrinous - when vascular leaks are large or there is a procoagulant stimulus in the serum eg cancer cells – resolution – scarring if fibrin is not removedorganisation • Suppurative or purulent – large amts of pus or purulent exudate consists of neutrophils, necrotic cells& edema fluid.org- staphylococci- called pyogenic ( pus producing )bacteria eg acute appendicitis. Abscesses –focal localised collection of purulent inflammatory tissue walled by connective tissue.

Contd… • Ulcer- a local defect or excavation of the surface of an organ or tissue that is produced by sloughing ( shedding) of inflammatory necrotic tissue. • Inflammatory necrosis of mucosa of mouth, stomach, intestines or genitourinary tract. • Subcutaneous inflammations of the lower extremities in older persons with circulatory disturbances that predispose to extensive necrosis. • Acute- intense PMN infiltration & vascular dilation in the margins of the defect. • Chronic- margins & base of ulcer develop fibroblastic proliferation , scarring & accu of lymp , macrophages & plasma cells.

Systemic effects of inflammatn • Fever- cytokines- IL-1,6 & TNF-alpha- produced by leucocytes in response to infectious agents or toxins or immune comp • Leukocytosis- esp in bacterial infection 15-20000 cells /ml . • leukemoid reactions- 40 –100000 cells/ml • Shift to left • Leukopenia- typhoid fever& infections caused by viruses, rickettesiae & certain protozoa

Tissue repair • It involves 2 distinct processes• 1) regeneration- replacement of injured cells by cells of same type,no trace of injury • 2)replacement by connective tissue–fibrosis which leaves a permanent scar. • Regeneration depends on type of cells• a)