Acute Inflammation

Cardinal Signs (Celsus + Virchow)

Three Major Components

1. Dilation of small vessels - leading to increased blood flow
2. Increased vascular permeability - enabling plasma proteins and leukocytes to leave the circulation
3. Emigration and activation of leukocytes - to accumulate at the focus of injury and eliminate the offending agent

Vascular Reactions

Changes in Vascular Flow and Caliber

1. Vasodilation - Earliest manifestation. Induced chiefly by histamine acting on vascular smooth muscle of postcapillary venules. Causes redness (rubor) and warmth (calor).
2. Increased vascular permeability - Quickly follows vasodilation. The principal mechanism is contraction of endothelial cells, creating interendothelial openings. Elicited by histamine, bradykinin, and leukotrienes. Occurs within 15-30 minutes and is usually short-lived. In severe injury (burns), direct endothelial damage causes immediate, sustained leakage.
3. Stasis - Loss of fluid and increased vessel diameter slow blood flow. Red cells concentrate in small vessels, increasing viscosity → vascular congestion.
4. Margination and adhesion - With stasis, leukocytes (mainly neutrophils) accumulate along the endothelium, adhere to upregulated adhesion molecules, and migrate into tissue.

Key Terms

• Exudate: Extravascular fluid with high protein concentration and cellular debris - implies increased vascular permeability (inflammation)
• Transudate: Fluid with low protein content (mostly albumin), essentially an ultrafiltrate - osmotic/hydrostatic imbalance without inflammation
• Edema: Excess fluid in interstitial tissue or serous cavities (can be exudate or transudate)
• Pus: Purulent exudate rich in neutrophils, dead cell debris, and microbes

Leukocyte Recruitment

Step 1: Rolling (Selectins)

• Loose, reversible attachment to endothelium
• Mediated by selectins (E-selectin, P-selectin on endothelium; L-selectin on leukocytes) binding to carbohydrate ligands
• TNF and IL-1 upregulate selectin expression on endothelium

Step 2: Firm Adhesion (Integrins)

• Stable adhesion mediated by integrins on leukocytes (e.g., LFA-1, Mac-1) binding to ICAM-1 on endothelium
• Chemokines increase integrin avidity (affinity state change via inside-out signaling)

Step 3: Transmigration (Diapedesis)

• Leukocytes migrate through interendothelial junctions (mainly at postcapillary venules)
• CD31 (PECAM-1) plays a key role in this crossing

Step 4: Chemotaxis

• Directed migration toward the injury site along a chemical gradient
• Major chemotactic agents: C5a, IL-8 (CXCL8), leukotriene B4 (LTB4), bacterial products (fMLP)

Neutrophils vs. Macrophages

Phagocytosis and Killing

Phagocytosis - Three Steps

1. Recognition and attachment - facilitated by opsonins (IgG Fc, C3b) binding to specific leukocyte receptors
2. Engulfment - pseudopods extend around the particle, forming a phagosome
3. Killing and degradation - phagosome fuses with lysosome → phagolysosome

Intracellular Killing

• Reactive oxygen species (ROS): NADPH oxidase generates superoxide → H₂O₂ → hypochlorous acid (HOCl) via myeloperoxidase (MPO). This is the "respiratory burst."
• Nitric oxide (NO): Generated by iNOS in macrophages; reacts with superoxide to form peroxynitrite (ONOO⁻)
• Lysosomal enzymes: Elastase, collagenase, cathepsins - active at acid pH

Neutrophil Extracellular Traps (NETs)

• Extruded chromatin meshworks containing histones and antimicrobial proteins (elastase, MPO)
• Trap and kill microbes extracellularly
• Also contribute to tissue injury and thrombosis

Mediators of Inflammation

Arachidonic Acid Pathway (Key for Pharmacology)

• COX pathway → Prostaglandins and thromboxanes - blocked by NSAIDs (aspirin, ibuprofen)
• Lipoxygenase pathway → Leukotrienes - blocked by zileuton (5-LOX inhibitor) and montelukast (LT receptor antagonist)
• Phospholipase A₂ (releases AA from membrane) - blocked by corticosteroids (via lipocortin/annexin-1)

Complement System

• Classical pathway: Antigen-antibody complexes → C1 activation
• Alternative pathway: Microbial surface molecules directly activate C3
• Lectin pathway: Mannose-binding lectin (MBL) binds microbial carbohydrates

• C3a, C5a: Anaphylatoxins - stimulate mast cell degranulation, increase vascular permeability, vasodilation
• C5a: Potent neutrophil/monocyte chemotactic agent
• C3b: Opsonin - promotes phagocytosis
• MAC (C5b-9): Cell lysis (important for thin-walled organisms like Neisseria)

Morphologic Patterns of Acute Inflammation

1. Serous Inflammation

• Outpouring of watery, serum-like fluid into body cavities or spaces created by cell injury
• Few cells, no microbes
• Example: skin blister (burn/viral), pleural/pericardial effusion

2. Fibrinous Inflammation

• Greater vascular permeability allows fibrinogen to escape → fibrin deposited in extracellular space
• Characteristic of inflammation in body cavity linings
• Example: fibrinous pericarditis ("bread and butter" pericarditis), fibrinous pleuritis
• May undergo resolution (fibrinolysis) or organization (fibrosis → adhesions)

3. Purulent (Suppurative) Inflammation

• Formation of pus - neutrophils, liquefactive necrosis debris, microbes
• Caused mainly by pyogenic bacteria (S. aureus, Streptococcus)
• Abscess: Localized collection of pus surrounded by a wall of inflammatory tissue
• Example: staphylococcal abscess, brain abscess

4. Ulcer

• A discontinuity in the epithelium with underlying acute and chronic inflammation
• Example: peptic ulcer, pressure sore, diabetic foot ulcer

Termination of Acute Inflammation

• Mediators are short-lived (quickly decay, inactivated by enzymes, or scavenged)
• Neutrophils are short-lived and undergo apoptosis
• Anti-inflammatory substances are activated (lipoxins, IL-10, TGF-β, resolvins/protectins from omega-3 FAs)

Outcomes of Acute Inflammation

Summary Box

Acute inflammation = vascular dilation + increased permeability + leukocyte emigration (mainly neutrophils). Orchestrated by cell-derived (histamine, leukotrienes, prostaglandins, cytokines) and plasma-derived (complement, kinins) mediators. The cardinal signs (rubor, calor, tumor, dolor, functio laesa) arise from these vascular and cellular events. Resolution restores normal tissue; failure to eliminate the cause leads to abscess, scarring, or chronic inflammation.

Phagocytosis and Clearance of the Offending Agent

Neutrophils vs. Macrophages - Key Differences

Phagocytosis - Three Sequential Steps

Step 1: Recognition and Attachment

• Mannose receptor - a lectin that binds terminal mannose and fucose residues on microbial glycoproteins/glycolipids. Mammalian glycoproteins have terminal sialic acid or N-acetylgalactosamine instead, so this receptor selectively recognizes microbes, not host cells.
• Scavenger receptors - bind oxidized/acetylated LDL and a variety of microbes
• MAC-1 (CD11b/CD18, integrin) - also binds microbes for phagocytosis

Role of Opsonins (Critical Efficiency Boost)

Step 2: Engulfment

Step 3: Killing and Degradation

Intracellular Destruction Mechanisms

1. Reactive Oxygen Species (ROS) - Respiratory Burst

1. Activation assembles NADPH oxidase (phagocyte oxidase) on the phagolysosome membrane
2. NADPH oxidase reduces O₂ to superoxide anion (O₂•⁻)
3. Superoxide is converted to H₂O₂
4. Myeloperoxidase (MPO) in azurophil (primary) granules + Cl⁻ → converts H₂O₂ to hypochlorite (ClO⁻), a potent antimicrobial that kills by halogenation and oxidation of proteins/lipids
5. H₂O₂ + Fe²⁺ (Fenton reaction) → hydroxyl radical (•OH) - another powerful destructive agent

The H₂O₂-MPO-halide system is the most efficient bactericidal system of neutrophils.

Clinical link: Genetic defects in NADPH oxidase (phagocyte oxidase) cause chronic granulomatous disease (CGD) - an immunodeficiency characterized by recurrent bacterial and fungal infections and granuloma formation, because phagocytes can engulf but cannot kill microbes.

2. Reactive Nitrogen Species (RNS) - Nitric Oxide

• iNOS (inducible nitric oxide synthase) is upregulated in macrophages in response to microbial products and IFN-γ
• iNOS converts arginine → NO
• NO + O₂•⁻ → peroxynitrite (ONOO⁻) - a highly reactive molecule that attacks and damages lipids, proteins, and nucleic acids of microbes
• Mainly operative in macrophages (neutrophils produce little/no NO)

3. Lysosomal Granule Enzymes

• Acid proteases - degrade bacteria and debris within the acidified phagolysosome
• Neutral proteases (elastase, collagenase) - degrade extracellular components (collagen, basement membrane, fibrin, elastin, cartilage) - causing tissue destruction
• Lysozyme - hydrolyzes the muramic acid-N-acetylglucosamine bond in bacterial glycoprotein coat
• Lactoferrin - iron-binding protein (deprives bacteria of iron)
• Defensins - cationic arginine-rich peptides that are directly toxic to microbes
• Cathelicidins - antimicrobial proteins in neutrophils and other cells
• Major basic protein (eosinophils) - cytotoxic to helminths

• α₁-antitrypsin - major inhibitor of neutrophil elastase. Deficiency → uncontrolled elastase → emphysema (lung elastic fiber destruction)
• α₂-macroglobulin - antiprotease in serum/secretions

Neutrophil Extracellular Traps (NETs)

• Antimicrobial peptides (defensins)
• Enzymes: MPO, elastase

1. ROS-dependent activation of an arginine deaminase converts arginines → citrulline
2. Chromatin decondensation begins
3. MPO and elastase enter the nucleus → further chromatin decondensation
4. Nuclear envelope ruptures → chromatin is extruded
5. Neutrophil loses its nucleus and dies (NETosis)

• Trap and kill bacteria and fungi extracellularly
• Detected in blood during sepsis
• NETs can cause collateral tissue damage - NET-derived histones are cytotoxic and contribute to endothelial injury
• NETs promote thrombosis - implicated in some vascular diseases

Leukocyte-Mediated Tissue Injury

1. Inflammation is triggered by non-degradable stimuli (e.g., urate crystals in gout, silica in silicosis)
2. Frustrated phagocytosis - when phagocytes encounter materials too large to ingest (e.g., immune complexes on glomerular basement membranes), they are strongly activated and release lysosomal enzymes extracellularly
3. Autoimmune disease - host tissues are attacked
4. Hypersensitivity reactions (allergy, asthma) - response to harmless environmental antigens

The mechanisms that function to eliminate microbes (physiologic role) are also capable of damaging normal tissues (pathologic consequence).

• Controlled secretion during normal leukocyte activation
• Frustrated phagocytosis
• Phagolysosome membrane damage (e.g., by urate crystals)

Other Functional Responses of Activated Leukocytes (Macrophages)

• Produce cytokines (TNF, IL-1, IL-12) - amplify or limit inflammation
• Produce growth factors (VEGF, PDGF, TGF-β) - stimulate endothelial cells and fibroblasts
• Secrete enzymes (collagenase, MMP) - remodel connective tissue
• Initiate tissue repair and scar formation

Summary Box

Phagocytosis proceeds through recognition (via mannose receptor, scavenger receptors, or opsonin receptors for IgG and C3b) → engulfment (phagosome formation via actin polymerization) → killing (ROS via NADPH oxidase, NO via iNOS, lysosomal enzymes in the phagolysosome). NETs provide an additional extracellular trapping mechanism. The same weapons used against microbes can damage host tissue if directed inappropriately.