inflammation 2

chronic inflammation

chronic inflammation

• prolonged process lasting weeks/months

• continuing inflammation, tissue destruction, and attempts at repair occur simultaneously, in varying combinations

hallmarks of chronic inflammation

• mononuclear cell infiltration

• tissue destruction/ necrosis

• repair, including new vessel formation (angiogenesis) & fibrosis

causes of chronic inflammation

• persistent infection by microorganisms that resist immune responses

• hypersensitivity diseases (excessive immune responses against self antigens or commonly harmless environmental antigens

• prolonged exposure to toxic agents (exogenous/endogenous)

3 main features of chronic inflammation

• infiltration w/ mononuclear cells

• parenchyma destruction due to persistent offending agent and/or inflammation

• attempts at healing by connective tissue replacement and new blood vessel formation (angiogenesis)

macrophages are derive from

circulating form (monocytes)

macrophages in chronic inflammation

• phagocytose microbes & dead host cells

• secrete inflammatory mediators →initiate & sustain inflammation

• present antigens to T cells & respond to T signals → drive cell mediated immunity

in chronic inflammatory sites, more macrophages are recruited, and IFN-y drives

fusion into multinucleated giant cells

Th1 (IFN-y)

M1 macrophage activation → pro-inflammatory

Th2 (IL4, IL13)

M2 activation → repair/anti-inflammatory

Th2 (IL5)

eosinophils

Th17 (IL17)

recruits neutrophils & monocytes

Eosinophils

• present in IgE mediated rxns (allergies) & parasitic infections

• Recruited by eotaxin

• Release granule proteins

Dual role of eosinophils

• protective →parasitic killing

• Pathologic → tissue injury

Both contributes to chronic inflammation

Cytokines

• TNF-a, IL1, IL6

• Sustains systemic & local inflammatory signaling

Chemokines

• CCL2 (MCP-1), CXCL8(IL8

• Continuously recruits monocytes/macrophages & neutrophils

Growth factors

• TGF-B, VEGF

• Drives tissue scarring (fibrosis) & new blood vessel growth (angiogenesis)

Proteases

• tryptase, chymase

• Degrades tissue scaffolding, facilitating cell migration & remodeling

Neutrophils

• usually the hallmark of ACUTE inflammation

• Some forms of chronic inflammation continue to show neutrophilic infiltrates d/t persistent microbes, necrotic tissue, cytokines from activated macrophages & T cells

Acute on Chronic inflammation

Chronic inflammation that show neutrophilic infiltrates d/t ongoing infections, necrotic tissues, cytokines from activated macrophages & T cells

Granulomatous inflammation

Specific form of chronic inflammation characterized by focal accumulation of macrophages around an offending focus that is difficult to eradicate

Immune granulomas

• d/t chronic infection

• Persistent T-cell mediated immune response is elicited

Foreign body granulomas

• d/t large inert foreign bodies

• Do NOT incite an adaptive immune response

Immune granulomas are caused by

Prolonged macrophage T-cell interactions

What is the hallmark of granulomatous inflammation

Epithelioid cells

Foreign body giant cells

Foreign agent or other undigestible material that persists in the cytoplasm & multiple nuclei randomly scattered throughout the cytoplasm

Tuberculosis

• mycobacterium tuberculosis

• Caseating granuloma; acid-fast bacilli

Acute phase response

• inflammation is associated w/ cytokines-mediated systemic manifestations

• Controlled, physiologic responses that promote host defense & restoration of homeostasis

• Clinical & pathologic features: fever, leukocytosis, increased synthesis of acute phase proteins

During fevers, exogenous pyogenes stimulate macrophages to release

IL1 & TNF (endogenous pyrogens)

Leukocytosis

• WBC count reaches 15,000 to 20,000 WBC/uL

• Initially caused by an accelerated release of leukocytes from bone marrow post mitotic reserve (increase immature neutrophils in blood) mainly caused by IL1, TNF, IL6

Leukemoid rxn

Extreme elevation of WBCs (40,000 to 100,000)

Bacterial infections

Increase blood neutrophil count

Certain viral infections

Increase blood lymphocytes count

Allergies & parasitic infections

Increase blood eosinophil count

Acute phase proteins

• acute phase reactants

• Plasma proteins primarily synthesized in the liver that increase several hundred fold in response to inflammatory stimuli (notable IL6)

C-reactive protein (CRP)

• acts as an opsonin, coating microbial cell walls → facilitating their phagocytosis

• Activates the complement system → formation of MAC → direct lysis of pathogens

Serum amyloid A (SAA) protein

• act as an opsonin → increase phagocytosis

• Prolonged elevation → amyloidosis

Amyloidosis

Serious condition where SAA derived fibrils deposit in organs

Fibrogen

Coagulation factor that converts to fibrin → binds to RBCs, causing increase erythrocyte sedimentation rate (ESR)

Systemic Inflammatory Response Syndrome (SIRS)

• exaggerated widespread inflammatory response

• Triggered by infections/ noninfectious insults such as trauma, burns, or pancreatitis

• Diagnostic criteria for SIRS (>2 met)

Diagnostic criteria for SIRS

• fever (>100.4 F or 38 C) or hypothermia (<96.8F/36C)

• Tachycardia (>90 bpm)

• Tachypnea (>20 breaths/minute)

• WBC count reaches>12,000/uL or <4,000/uL

Cytokines storm (hypercytokinemia)

• triggers: severe infections, certain immunotherapies, auto inflammatory conditions

• Acute systemic inflammatory response driven by excessive pro-inflammatory cytokines (TNF-a, IFN-y & IL1)

• Positive feedback loop amplifies the inflammatory cascade

• Impact: leads to SIRS, multi organ dysfunction, or death