Acute Inflammation

Historical Perspectives

earliest reference to inflammation in medical literature (1650 BC, Egypt) in the Smith Papyrus

associated inflammation with heat via symbol of flame

Ancient Greeks used a term which meant inflammation also indicating a hot thing

The greek term persists in our word "phlegmon" used to describe internal inflammatory lesions

Cornelius Celsus(1^st century AD Rome): cardinal signs of inflammationÞ redness, swelling, heat, pain

Rudolf Virchow(19^th century AD Rome): added a fifth cardinal sign Þ loss of function

The Cellular Theory of Inflammation (mid-19^th century)

Julius Cohnheim Þ observed vasomotor effects and leukocyte emigration in sites of inflammation

Elie Metchnikoff Þ first described phagocytosis

Paul Ehrlich Þ Humoral Theory of Inflammation Þ defined role of Ab in host defenses

Modern understanding of inflammation admits roles for both cellular and soluble (humoral) factors

Acute vs Chronic Inflammation

distinguished by time course of inflammatory response and by histopathological differences

acute inflammation (early phase of response) involves polymorphonuclear neutrophil leukocytes as the principle cellular effectors

chronic inflammation (occurs over long time) involves monocytes, macrophages, lymphocytes and plasma cells (collectively, mononuclear leukocytes)

acute inflammation, chronic inflammation, repair Þ follow one another in most inflammatory lesions

no sharp boundaries in space or time among these processes

Key Events in Acute Inflammation

Vascular Events

Increased Blood Flow

From relaxation of terminal arterioles in the inflammatory lesion
Produces local erythema (rubor) and heat (calor)

Increased Vascular Permeability

From contraction of capillary endothelial cells

Mildest form: extravasation of water and low molecular weight solutes
More severe: extravasation of water, low and high molec wght solutes (plasma proteins)
Most severe: extravasation of water, low and high molec wght solutes and blood cells

Leads to local swelling (tumor)

Leukocyte Events

Margination: neutrophils pass thru inflamed vascular beds, attach to vessel wall and roll with current

Mediated by expression of binding sites on activated endothelial cells for neutrophil surface glycoproteins

Diapedesis: after rolling along endothelial surface, the neutrophil attaches to insinuate itself between 2 endothelial cells and pass thru the basement memb into the extravascular tissues

Requires the activation of neutrophil adhesion molec and the active motility of the neutrophil

Chemotaxis: once free in the extravascular space, the neutrophil senses minute conc gradients of chemoattractants, and orients its migration to approach the source of the gradient

Margination, diapedesis, chemotaxis deliver leukocytes to an inflammatory focus within hours

Cellular acute inflam exudate containing polymorphonuclear leukocytes and necrotic debrisÞ pus

Phagocytosis: upon encountering a foreign particle, a neutrophil engulfs the particle and attempts to digest it by releasing enzymes into the phagolysosome

Degranulation: even in absence of particles for phagocytosis, an overstimulated neutrophil will release enzymes and other toxic intermediates into the extracellular space (can cause severe tissue damage with temporary or permanent loss of function Þ double edged sword)

Physiological Significance

mechanisms for the cardinal signs of inflammation

Ý blood flow Þ redness (rubor) and heat (calor)

Ý vascular permeability Þ swelling (tumor)

nerve stimulation Þ pain (dolor)

tissue destruction Þ loss of function (functio laesa)

component events of acute inflam work together to alleviate the noxious stimulus and promote healing

vascular events locally increase supply of cellular and humoral effectors at immediate site of inflam

cellular events work to engulf, kill, and digest the stimulus so the area can be cleared for repair process

Chemical Mediators of Acute Inflammation

Proteins

Complement Components

Classical pathway mediates specific activation by Ag-Ab complexes Þ C4b2a Þ C4b2a3b Þ C5b-9

Alternative pathway mediates nonspecific activation on microbial surfaces Þ C3bBb Þ C3bBbC3b Þ C5b-9

Classical and Alternative paths have similar intermediates with proinflammatory properties

The Anaphylatoxins (C5a and C3a): powerful effects on vascular permeability; mediators of neutrophil activation, chemotaxis and degranulation

Opsonin (C3b): promotes receptor-mediated phagocytosis by neutrophils

Bradykinin (Hageman Factor activates Kallikrein which cleaves Kininogen into Bradykinin (9 aa fragment))

Effects: Ý vascular permeability, vasodilation, pain; Inactivated by angiotensin converting enzyme (ACE)

Lipids

sn-1-alkyl phospholipids in memb. of inflam. cells + Phospholipase A2 Þ arachidonate + sn-1-alkyl-2-lysophospholipid

arachidonate Þ eicosanoids (Prostaglandins and Leukotrienes)

Prostaglandins (biosynthesis begins with arachidonate cyclooxygenase)

Mediate diverse functions: platelet inactivation/activation, pain, vasoconstriction/dilation

Leukotrienes (biosynthesis begins with arachidonate 12-lipoxygenase or arachidonate 5-lipoxygenase)

Mediate diverse proinflammatory functions: metabolic, chemotaxis, pain, vasoconstriction, bronchoconstriction and vascular permeability

sn-1-alkyl-lysophospholipids Þ acylationÞ platelet activating factor

important mediator of anaphylaxis: Platelet Aggregation, Leukocyte Activation and Chemotaxis, Vasoconstriction, Vascular Permeability, Shock

Other

Histamine (Formed by decarboxylation of histidine)

Stored in granules of platelets, basophils and tissue mast cells before release
Powerful mediator of vascular permeability, pain, arteriolar dilatation and arterial contraction

Serotonin

stored preformed in platelet, basophil and mast cell granules
Causes vasoconstriction or vasodilatation, platelet aggregation

Nitric Oxide (Formed from arginine by NO synthases present in endothelium (constitutive) and macrophages (inducible))

The canonical oxide O=N-N=O dissociates into short-lived free radicals · N=O

Actions of NO in vivo are caused by stable S-nitroso compounds (R-SNO) formed by reaction of NO with free thiols

Actions in vivo: Vasodilator, Anti-platelet aggregation, Cytotoxic/antimicrobial

Endotoxin (bacterial cell wall lipopolysaccharides)

Complement activation thru alternative pathway; Stimulator of monokine secretion by activated macrophages

N-Formyl-Methionyl Peptides

attracts neutrophils to sites where lysis of bacteria (or mitochondria) has begun

Cytokine Proteins in Chronic Inflammation

Interleukin-8

Product of macrophages and endothelium; Activates neutrophils; Mediates neutrophil and lymphocyte chemotaxis

Interleukin-1 (The prototypical "monokine")

Produced by macrophages, NK cells, smooth muscle cells and epithelial cells
Mediates protean cellular and systemic effects associated with inflammation including activation of lymphocytes for mitotic stimulation, fever, increased vascular permeability, scarring, neutrophil activation, and many others

Interleukin-6

A pyrogen and inducer of acute phase proteins; Produced by both lymphocytes and monocytes

TNFa – (Tumor Necrosis Factor-a )

Causes hemorrhagic necrosis of certain tumors in vivo, and cell death by apoptosis of some tumor cells in vitro
Produced by macrophages; Mediates fever, vascular permeability, cachexia, leukocytosis and pleocytosis

Systemic Effects of Inflammation (Acute Phase Reactants)

Macrophages produce IL-1, TNF-a , and IL-6; T-lymphocytes produce IL-6 and TNF; Fibroblasts produce IL-6 and IL-1

Fever: IL-1, TNF-a , and IL-6 act in the CNS to alter thermoregulation

Leukocytosis/Pleocytosis

Leukocytosis: Ý # of (mostly) neutrophil leukocytes in the blood; Mediated directly by IL-1 and TNF-a

Pleocytosis: Immature neutrophil leukocytes enter the blood; Called "left shift" ; Mediated indirectly by IL-1 and TNF-a by induction of GM-CSF

Induction of Acute Phase Proteins

IL-1, TNF-a , and/or IL-6 Ý synthesis of several plasma proteins: Complement Components- C3, Factor B; Protease Inhibitors- a 1-antichymotrypsin, a 2-macroglobulin; Binding Proteins- C Reactive Protein, haptoglobin, hemopexin; Coagulation Factors- Fibrinogen; Others- Serum Amyloid A, Serum Amyloid P

Acute phase protein induction correlates with increase in Erythrocyte Sedimentation Rate

Cachexia: causes: Anorexia, Ý protein breakdown, Ý triglyceride mobilization from fat cells