INFLAMMATIONINFLAMMATIONDR NADEEM REYAZ

UNIVERSITY OF HEALTH SCIENCES

EDUCATION IS EDUCATION IS HANGING HANGING AROUND AROUND

UNTIL YOU’VE UNTIL YOU’VE CAUGHT ONCAUGHT ON

Charles DarwinCharles Darwin

INFLAMMATIONINFLAMMATION

is the reaction of a tissue and its is the reaction of a tissue and its microcirculation to a pathogenic microcirculation to a pathogenic insult or it is a reaction which is insult or it is a reaction which is

characterized by the generation of characterized by the generation of inflammatory mediators and amount inflammatory mediators and amount

of fluid and leucocytes from the of fluid and leucocytes from the blood into extra vascular tissue blood into extra vascular tissue

FOUR CARDINALFOUR CARDINAL SIGNS OF SIGNS OF INFLAMMATIONINFLAMMATION

►Rubor (redness)Rubor (redness)►Color (heat)Color (heat)►Tumor (swelling)Tumor (swelling)►Dolar (pain)Dolar (pain)

Aulus CelsusAulus Celsus

Roman Roman EncyclopedistEncyclopedist

INFLAMMATION PROCEEDS AS INFLAMMATION PROCEEDS AS FOLLOWSFOLLOWS

► INITIATION of the inflammatory INITIATION of the inflammatory response, in which localization and response, in which localization and clearance of foreign substances and clearance of foreign substances and onset of stimuli take placeonset of stimuli take place

►AMPLIFICATION of the inflammatory AMPLIFICATION of the inflammatory response, in which both soluble response, in which both soluble mediators and cellular inflammatory mediators and cellular inflammatory system are activated, follows system are activated, follows recognition of injuryrecognition of injury

►TERMINATION of the inflammatory TERMINATION of the inflammatory response, after generation of response, after generation of inflammatory agents and elimination inflammatory agents and elimination of the foreign agent, is accomplished of the foreign agent, is accomplished by specific inhibitors of the mediatorsby specific inhibitors of the mediators

                                                     :

CELLS OF INFLAMMATION

ACUTE INFLAMMATIONACUTE INFLAMMATION

► is a stereotyped response to recent is a stereotyped response to recent or ongoing injury. Although the or ongoing injury. Although the process is complex, the principal process is complex, the principal features are dilatation and leaking of features are dilatation and leaking of vessels, and involvement of vessels, and involvement of circulating neutrophils circulating neutrophils

►The hallmarks of acute inflammation The hallmarks of acute inflammation are are

►(1) vasodilatation and increased (1) vasodilatation and increased vascular permeability; vascular permeability;

►(2) entry of neutrophils into the (2) entry of neutrophils into the tissues. tissues.

► Sequence of Acute Inflammation

► Vascular changes transient► vasoconstriction of arterioles► vasodilation► of arterioles leading to increased blood flow

increased► permeability, loss of fluid, concentration of red

cells,► increased blood viscosity, and slowing of

circulation (stasis)

►HyperemiaHyperemia is a generic term for is a generic term for extra blood in an organ due to extra blood in an organ due to dilation of the arterioles dilation of the arterioles

►Edema► Increased vascular permeability hallmark

of acute inflammation► Loss of protein reduced intravascular

osmotic pressure, increased extravascular osmotic pressure

► Increased hydrostatic pressure from vasodilation

► Increased extravascular fluid – edema

►Leaky Endothelium

►Gaps between endothelial cells►Direct endothelial cell injury►Chemical mediators histamine,

bradykinin, leukotriences, complement,

►Cellular Changes

►Neutrophils►Margination►Rolling►Adherence/pavementing►Transmigration (diapedesis)►Migration toward chemotactic stimulus

►EmigrationEmigration ("diapedesis") ("diapedesis") of of neutrophils from the vessels into the neutrophils from the vessels into the tissues occurs when the cells squeeze tissues occurs when the cells squeeze through the widened endothelial cell through the widened endothelial cell gaps, then get through the basement gaps, then get through the basement membrane by digesting it with membrane by digesting it with enzymes enzymes

►Adhesion and transmigration

► Binding of adhesion molecules on WBC and endothelial cell modulated by chemical mediators

► Endothelial adhesion receptors: selectins (E,P,L), immunoglobulin family molecules (ICAM1, VCAM1), WBC receptors, integrins (CD11/18, VLA04), mucin like glycoproteins

► Migration of PMN across endothelium (transmigration) CD31

►Chemotaxis

►WBCs move toward site of injury under influence of chemoattractants

►exogenous: bacterial products►endogenous: complement components

(C5a), products of lipoxygenase pathway (LTB4), cytokines (e.g., IL8)

►Phagocytosis by PMN, Macrophages►Recognition and attachment►opsonins (Fc fragments, C3b, C3bi)►receptors (IgG Fc, CR13)►· Engulfment►· Killing or degradation (e.g. H202)►· Release of WBC products (lysosomal

enzymes, 02 metabolites, AA metabolites)

Acute inflammation - Acute pneumonia - lung. Almost every alveolar space is filled with cellular infiltrate. There is hardly any air space left in the lung

Acute inflammation - Acute pneumonia - lung. An abundance of eosinophilic material (neutrophils) with fine strands are present in the alveolar space.

Inflammatory infiltrate, fluid with fibrin into the alveolar spaces

Acute fibrinous pericarditis

the yellowish fluid in this

opened pericardial cavity is a purulent exudate.

Multifocal, suppurative, hepatitis

Acute, suppurative, pneumonia

Infective endocarditis (bovine)

Chemical Mediators of Inflammation

►Vasoactive amines (preformed)►histamine►mast cells, basophils, platelets►dilation of arterioles, increased

Permeability of venules►Serotonin (5hydroxytryptamine)►platelets, enterochromaffin cells►increased vascular permeability

► Plasma proteases► Complement C3a, C5a (C4a)► Anaphylatoxins increase vascular

permeability/vasodilation (via histamine)► C5a chemotactic for PMN, monocytes,

basophils► increase adhesion to endothelium (activates

WBC)► C3b/bi opsonins

►The complement systemThe complement system is a group is a group of 20 plasma proteins which are of 20 plasma proteins which are activated in cascades by the classic or activated in cascades by the classic or alternate pathways alternate pathways

►Kinins (cascade activated by factor XIIa)Bradykinin (increased permeability,

vasodilation)

►BradykininBradykinin increases vascular increases vascular permeability, dilates blood vessels, permeability, dilates blood vessels, contracts non-vascular smooth contracts non-vascular smooth muscle, and causes pain. muscle, and causes pain.

►Clotting system

Thrombin (increased WBC adhesion)

Factor Xa (increased permeability, WBC exudation)

►Fibrinolytic system

Fibrin split products (increased permeability)

►Arachidonic acid metabolites►Cyclooxygenase pathway►prostaglandins (vasodilation,

potentiate edema)►prostacyclins (vasodilation, plt aggreg)►thromboxane (vasoconstr, plt aggreg)►Lipoxygenase pathway

►ProstaglandinsProstaglandins: products of the : products of the cyclooxygenase pathway of cyclooxygenase pathway of arachidonic acid metabolism arachidonic acid metabolism

►ProstacyclinProstacyclin (PGI2), (PGI2), from the vessel from the vessel wall, prevents platelet aggregation, wall, prevents platelet aggregation, dilates vessels dilates vessels

►leukotrienes (increased permeability, vasoconstriction, bronchospasm)

►LeukotrienesLeukotrienes:: products of the products of the lipooxygenase pathway of arachidonic lipooxygenase pathway of arachidonic acid metabolism. They are produced acid metabolism. They are produced by all of the inflammatory cells except by all of the inflammatory cells except lymphocytes lymphocytes

►Platelet activating factor►vasodilation, increased permeability►Increased WBC adhesion (increased

integrin binding)►chemotaxis►Platelets aggregation

►Cytokines► Proteins produced by many cell types that

modulate functions of other cells► interleukin1/ tumor necrosis factor► acute phase reaction (fever, neutrophilia)► endothelial activation

►Nitric oxide► From macrophage/endothelium –

vasodilatation

Outcomes of Acute Inflammation

►Complete resolution►Fibrosis►Granulation tissue

capillaries macrophages, fibroblasts

►Collagen-contracts to scar►Abscess►Chronic Inflammation

Granulation tissue, healing wound

LUNG ABSCESS

ABSCESS MICROSCOPIC PICTURE

Myocardial Abscess

Chronic inflammationChronic inflammation

►("late-phase inflammation") is a ("late-phase inflammation") is a response to prolonged problems, response to prolonged problems, orchestrated by T-helper lymphocytes. orchestrated by T-helper lymphocytes. It may feature recruitment and It may feature recruitment and activation of T- and B-lymphocytes, activation of T- and B-lymphocytes, macrophages, eosinophils, and/or macrophages, eosinophils, and/or fibroblasts fibroblasts

Lymphocytes and Plasma cells

Eosinophils and Lymphocytes

                                                    

•Lymphoid nodule •Fibrosis •Alveolar spaces

Chronic inflammation-Lung

Features of Chronic Features of Chronic inflammationinflammation

Mononuclear cell infiltration

►Monocytes—transform to macrophages in connective tissue—“activated” macrophages

►lymphocytes►plasma

Mixed inflammatory infiltrate (Plasma cell, Macrophages and

Eosinophils)

Chronic cystitis

Chronic cystitis (lymphocytic cystitis)

►Tissue destruction-repair granulation tissue

-formation of blood vessels (angiogenesis)-fibroblast proliferation

►Collagen deposition/scarring

Chronic nephritis, kidney is atrophied and fibrotic

Morphologic patterns of acute and chronic inflammation

►Purulent, or suppurative: neutrophils (PMNs) predominate

►Fibrinous: abundant fibrin, usually involving serosal surfaces, e.g. pericardium

►Serous: abundant fluid ,e.g. skin blister

Systemic Effects of Inflammation

►Fever (IL1, IL6, TNF, prostaglandins)►Malaise►Pain►Rapid Pulse

►Labs Findings: -neutrophilia in blood -increased erythrocyte sedimentation

rate ---increased acute phase reactants (e.g. C reactive protein, complement)

Granulomatous inflammationGranulomatous inflammation

►A distinctive pattern of chronic A distinctive pattern of chronic inflammatory reaction in which the inflammatory reaction in which the predominant cell type is an activated predominant cell type is an activated macrophage with a modified epithelial macrophage with a modified epithelial like (epithelioid) appearance.like (epithelioid) appearance.

► a special kind of chronic inflammation a special kind of chronic inflammation which occurs in the presence of which occurs in the presence of indigestible material and/or cell-mediated indigestible material and/or cell-mediated immunity ("type IV hypersensitivity“) immunity ("type IV hypersensitivity“)

►A granuloma is a focal area of A granuloma is a focal area of granulomatous inflammation. It granulomatous inflammation. It consists of a microscopic aggregation consists of a microscopic aggregation of macrophages that are transformed of macrophages that are transformed into epithelium like cells (epithelioid into epithelium like cells (epithelioid cells) surrounded by a collar of cells) surrounded by a collar of mononuclear leukocytes.mononuclear leukocytes.

GranulomaGranuloma

epithelioid cells

►Granulomas can contain syncytial Granulomas can contain syncytial giant giant cellscells (polykaryons). For our purpose, (polykaryons). For our purpose, there are two kinds of giant cells:there are two kinds of giant cells:

-Langhans giant cells have their nuclei -Langhans giant cells have their nuclei

arranged in a horseshoe around the edge,arranged in a horseshoe around the edge,

--foreign body giant cellsforeign body giant cells, with nuclei , with nuclei

dispersed more or less evenly dispersed more or less evenly

Langhan’s giant cells

Foreign body giant cells

Langhan’s type of giant cell

Granulomatous pneumonia, Langhans-type giant cell, epithelioid cells, lymphocytes, and fibrosis

Foreign body Granuloma

The classic granulomatous diseases The classic granulomatous diseases include tuberculosis, leprosy, foreign include tuberculosis, leprosy, foreign body reactions (*  including the body reactions (*  including the reactions to everything from sutures to reactions to everything from sutures to schistosome eggs), the deep fungal schistosome eggs), the deep fungal infections, berylliosis, and the infections, berylliosis, and the mysterious disease "sarcoidosis". mysterious disease "sarcoidosis".

►Granulomas with suppurationGranulomas with suppuration (i.e., with (i.e., with pus in their centers; "stellate pus in their centers; "stellate microabscesses") are typical of those microabscesses") are typical of those bacterial diseases with a propensity to bacterial diseases with a propensity to involve lymph nodes. These are involve lymph nodes. These are lymphogranuloma venereum, cat lymphogranuloma venereum, cat scratch fever, brucellosis, plague, scratch fever, brucellosis, plague, tularemia, glanders-melioidosis, listeria, tularemia, glanders-melioidosis, listeria, campylobacter, and yersinia infection campylobacter, and yersinia infection

►Granulomas with caseationGranulomas with caseation are typical are typical of certain fungal infections of certain fungal infections (histoplasmosis, blastomycosis, and (histoplasmosis, blastomycosis, and coccidioidomycosis, as above) and of coccidioidomycosis, as above) and of mycobacterial ("fungus-like bacteria") mycobacterial ("fungus-like bacteria") infections (basically TB, leprosy, and infections (basically TB, leprosy, and "atypical mycobacteria"). "atypical mycobacteria").

Granulomatous lymphadenitis

(Histoplasmosis)

lung with tuberculosis

lung with tuberculosis

Granulomatous pneumonia (tuberculosis)

Granulomatous pneumonia (tuberculosis), area of central necrosis, Langhans-type giant cells, fibrosis,

epithelioid cells

Caseous granulomatous inflammation-

LUNG

gross appearance of caseous

necrosis in a hilar lymph node infected with tuberculosis

Renal tuberculosis

Caseous granulomatous lymphadenitis

Carries Spine

►Granulomas with foreign bodiesGranulomas with foreign bodies: : aspirated food, schistosome eggs, aspirated food, schistosome eggs, toxocara, silicone injections, splinters, toxocara, silicone injections, splinters, sutures, windshield fragments, sutures, windshield fragments, chalazions, ruptured epidermoid cysts, chalazions, ruptured epidermoid cysts, sea urchin spines, mucus plugs in sea urchin spines, mucus plugs in cystic fibrosis, nitrogen bubbles cystic fibrosis, nitrogen bubbles ("pneumatosis"; "tissue emphysema"), ("pneumatosis"; "tissue emphysema"),

►dead aspergillus fungi, dead filaria, dead aspergillus fungi, dead filaria, ingrown hairs, talc in the lungs, ingrown hairs, talc in the lungs, metastatic calcification bits, uric acid metastatic calcification bits, uric acid crystals, sclerosing lipogranuloma of crystals, sclerosing lipogranuloma of the penis, insect bites, "actinic the penis, insect bites, "actinic elastolytic granuloma of Mieschler" (a elastolytic granuloma of Mieschler" (a foreign body reaction to your own foreign body reaction to your own elastic fibers), etc. elastic fibers), etc.

Cholesterol Granuloma

Silicotic Granuloma

Foreign Body Giant cell Granuloma

foreign body type giant cell at the upper left of center adjacent to a segment of vegetable

material aspirated into the lung

Two foreign body giant cells are seen just to the right of center where there is a bluish strand of

suture material

Other solid granulomasOther solid granulomas

►organic pneumoconioses, berylliosis, organic pneumoconioses, berylliosis, zirconium disease (the infamous zirconium disease (the infamous "armpit sarcoidosis"), Wegener's "armpit sarcoidosis"), Wegener's granulomatosis, Lennert's lymphoma, granulomatosis, Lennert's lymphoma, sarcoidosis, Crohn's disease, primary sarcoidosis, Crohn's disease, primary biliary cirrhosis, biliary cirrhosis, ToxoplasmosisToxoplasmosis and and Q-Q-feverfever and and cutaneous leishmaniasiscutaneous leishmaniasis etc etc

THE ENDTHE END