Chapter 3
Introduction
Inflammation is a fundamental response of the body to injury or infection. It represents a complex series of events that involves the vascular system, immune cells, and various molecular mediators. Understanding inflammation is crucial for comprehending the pathogenesis of numerous diseases, from acute infections to chronic autoimmune disorders.
This chapter explores the mechanisms, manifestations, and outcomes of inflammation, as well as the subsequent process of tissue repair. We will examine how the body's protective response can sometimes become harmful and how the balance between inflammation and repair determines the ultimate outcome of tissue injury.
Acute Inflammation
Acute inflammation is the immediate and early response to an injurious agent. It is a short-term process, typically occurring within minutes to hours, and is characterized by five cardinal signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain), and functio laesa (loss of function).
Vascular Changes in Acute Inflammation
The vascular response is a critical component of acute inflammation and consists of several sequential events:
Vasodilation
Occurs after a transient vasoconstriction
Mediated by histamine, prostaglandins, nitric oxide
Results in increased blood flow → redness and heat
Facilitates delivery of plasma proteins and leukocytes to the site of injury
Increased Vascular Permeability
Allows plasma proteins to escape into the extravascular space
Results in exudate formation → swelling
Mechanisms include:
Endothelial cell contraction (histamine, bradykinin)
Direct endothelial injury (burns, toxins)
Leukocyte-dependent injury (severe infections)
Increased transcytosis (VEGF)
Leakage from new blood vessels (angiogenesis)
Hemodynamic Changes
Initial increased blood flow due to vasodilation
Followed by slowing of circulation (stasis)
Peripheral orientation of leukocytes along vessel walls (margination)
Facilitates leukocyte adhesion and emigration
Cellular Events in Acute Inflammation
The cellular phase of acute inflammation involves the recruitment and activation of leukocytes, primarily neutrophils:
Leukocyte Extravasation
Leukocyte extravasation (migration from blood vessels into tissues) occurs through a multi-step process:
Margination and Rolling
Mediated by selectins (P-selectin, E-selectin on endothelium; L-selectin on leukocytes)
Weak, reversible interactions
Slows leukocytes in bloodstream
Adhesion
Mediated by integrins on leukocytes (LFA-1, Mac-1) and immunoglobulin superfamily members on endothelium (ICAM-1, VCAM-1)
Firm attachment to endothelium
Activated by chemokines
Transmigration (Diapedesis)
Movement between endothelial cells
Mediated by PECAM-1 (CD31)
Passage through basement membrane via secretion of collagenases
Chemotaxis
Directed movement toward chemical stimuli
Chemotactic factors include:
Bacterial products (formylated peptides)
Complement components (C5a)
Chemokines (IL-8)
Leukotriene B4
Platelet-activating factor
Phagocytosis
Once leukocytes reach the site of injury, they engulf and destroy microorganisms and debris through phagocytosis:
Recognition and Attachment
Enhanced by opsonization (coating with IgG, C3b)
Mediated by receptors for Fc portion of IgG and C3b
Pattern recognition receptors (mannose receptor, scavenger receptors)
Engulfment
Extension of pseudopods around particle
Formation of phagosome
Driven by actin polymerization
Killing and Degradation
Fusion of phagosome with lysosomes → phagolysosome
Oxygen-dependent mechanisms:
Respiratory burst → production of reactive oxygen species (ROS)
NADPH oxidase → superoxide anion
Myeloperoxidase → hypochlorous acid
Oxygen-independent mechanisms:
Lysosomal enzymes (proteases, hydrolases)
Defensins (antimicrobial peptides)
Lactoferrin (iron sequestration)
Defects in Leukocyte Function
Defects in leukocyte function can lead to increased susceptibility to infections:
Leukocyte Adhesion Deficiency (LAD)
Type I: Defect in β2 integrin (CD18)
Type II: Defect in fucose metabolism → impaired selectin ligand formation
Type III: Defect in kindlin-3 → impaired integrin activation
Clinical features: Delayed umbilical cord separation, recurrent bacterial infections, poor wound healing
Chronic Granulomatous Disease (CGD)
Defect in NADPH oxidase → impaired respiratory burst
X-linked (most common) or autosomal recessive
Clinical features: Recurrent catalase-positive bacterial and fungal infections, granuloma formation
Diagnosis: Nitroblue tetrazolium (NBT) test, dihydrorhodamine (DHR) flow cytometry
Chédiak-Higashi Syndrome
Defect in lysosomal trafficking regulator protein (LYST)
Autosomal recessive
Clinical features: Partial albinism, recurrent pyogenic infections, giant granules in leukocytes
Associated with accelerated phase (lymphohistiocytic infiltration of organs)
Chemical Mediators of Acute Inflammation
Inflammatory mediators are soluble molecules that initiate and regulate the inflammatory response:
Cell-Derived Mediators
Histamine
Stored in mast cells, basophils, platelets
Released in response to physical injury, complement components (C3a, C5a), immunologic reactions
Effects: Vasodilation, increased vascular permeability
Short-lived effect (minutes)
Serotonin (5-Hydroxytryptamine)
Stored in platelets, enterochromaffin cells
Released during platelet aggregation
Effects: Similar to histamine
Prostaglandins
Derived from arachidonic acid via cyclooxygenase (COX) pathway
COX-1 (constitutive) and COX-2 (inducible)
Effects: Vasodilation, pain, fever
Target of NSAIDs (inhibit COX enzymes)
Leukotrienes
Derived from arachidonic acid via lipoxygenase pathway
LTB4: Potent neutrophil chemoattractant
LTC4, LTD4, LTE4 (slow-reacting substance of anaphylaxis): Bronchoconstriction, increased vascular permeability
Important in asthma pathogenesis
Platelet-Activating Factor (PAF)
Produced by various cells (neutrophils, monocytes, endothelial cells)
Effects: Platelet aggregation, vasodilation, increased vascular permeability, bronchoconstriction
Potent inducer of anaphylaxis
Reactive Oxygen Species (ROS)
Produced during respiratory burst
Include superoxide anion, hydrogen peroxide, hydroxyl radical
Effects: Microbial killing, tissue damage
Neutralized by antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase)
Nitric Oxide (NO)
Produced by nitric oxide synthase (NOS)
Endothelial NOS (eNOS): Constitutive, vasodilation
Inducible NOS (iNOS): Produced by activated macrophages, microbial killing
Effects: Vasodilation, cytotoxicity
Cytokines
Produced by various cells, especially macrophages and lymphocytes
TNF-α, IL-1: Endothelial activation, fever, acute phase response
IL-6: Acute phase response, B cell activation
IL-8: Neutrophil chemotaxis
IL-12: NK cell activation, Th1 differentiation
Chemokines
Chemotactic cytokines
Classified based on position of cysteine residues (CC, CXC, CX3C, XC)
CXC chemokines (e.g., IL-8): Primarily attract neutrophils
CC chemokines (e.g., MCP-1): Primarily attract monocytes, lymphocytes
Plasma Protein-Derived Mediators
Complement System
Cascade of proteolytic enzymes
Activation pathways:
Classical: Antigen-antibody complexes
Alternative: Microbial surfaces
Lectin: Mannose-binding lectin on microbial surfaces
Effects:
Opsonization (C3b)
Chemotaxis (C5a)
Anaphylatoxins (C3a, C5a): Mast cell degranulation
Membrane attack complex (C5b-9): Cell lysis
Coagulation System
Activated during inflammation
Thrombin: Cleaves fibrinogen to fibrin, activates platelets
Factor XII (Hageman factor): Activates kinin system, complement
Kinin System
Bradykinin: Vasodilation, increased vascular permeability, pain
Produced by activation of Hageman factor
Morphologic Patterns of Acute Inflammation
The morphologic appearance of acute inflammation varies depending on the severity, cause, and specific tissue involved:
Serous Inflammation
Characterized by protein-poor fluid exudate
Minimal cellular component
Examples: Skin blister, pleural effusion in tuberculosis
Fibrinous Inflammation
Characterized by exudate rich in fibrinogen
Conversion to fibrin in tissues
Examples: Pericarditis ("bread and butter" appearance), pneumonia
Suppurative (Purulent) Inflammation
Characterized by production of pus (neutrophils, necrotic cells, edema fluid)
Typically caused by pyogenic bacteria
Examples: Abscess, empyema
Ulcers
Local defect in surface epithelium
Extends through epithelium into underlying tissue
Examples: Peptic ulcer, oral aphthous ulcer
Outcomes of Acute Inflammation
Acute inflammation can resolve in several ways:
Complete Resolution
Return to normal structure and function
Occurs when damage is minimal
Requires:
Removal of injurious stimulus
Neutralization of inflammatory mediators
Restoration of normal vascular permeability
Drainage of edema fluid and proteins
Abscess Formation
Localized collection of pus
Typically caused by pyogenic bacteria
Surrounded by inflamed tissue
May require surgical drainage
Healing by Fibrosis
Occurs when tissue damage is substantial
Replacement of normal parenchyma with connective tissue
Results in scar formation
Progression to Chronic Inflammation
Occurs when injurious agent persists
Characterized by mononuclear cell infiltration
May lead to tissue destruction and fibrosis
Chronic Inflammation
Chronic inflammation is a prolonged inflammatory response lasting weeks to months to years. It is characterized by the presence of mononuclear cells (lymphocytes, plasma cells, macrophages), tissue destruction, and attempts at repair occurring simultaneously.
Causes of Chronic Inflammation
Persistent Infections
Mycobacteria (tuberculosis, leprosy)
Some fungi (histoplasmosis)
Parasites (schistosomiasis)
Viruses (hepatitis B and C)
Prolonged Exposure to Toxic Agents
Silica (silicosis)
Asbestos (asbestosis)
Exogenous lipids (lipoid pneumonia)
Autoimmune Disorders
Rheumatoid arthritis
Systemic lupus erythematosus
Multiple sclerosis
Inflammatory bowel disease
Persistent Acute Inflammation
Inadequate clearance of injurious agent
Interference with normal healing process
Cells in Chronic Inflammation
Macrophages
Derived from blood monocytes
Key cells in chronic inflammation
Functions:
Phagocytosis
Antigen presentation
Cytokine production
Tissue remodeling
Activation states:
M1 (classical): Pro-inflammatory, induced by IFN-γ, LPS
M2 (alternative): Anti-inflammatory, tissue repair, induced by IL-4, IL-13
Lymphocytes
T lymphocytes: Cell-mediated immunity
CD4+ T helper cells: Cytokine production
CD8+ Cytotoxic T cells: Killing of infected cells
B lymphocytes: Humoral immunity, differentiate into plasma cells
Natural killer (NK) cells: Innate immunity, killing of infected or transformed cells
Plasma Cells
Derived from B lymphocytes
Produce antibodies
Characteristic appearance: Eccentric nucleus, clock-face chromatin, perinuclear halo
Eosinophils
Prominent in allergic reactions and parasitic infections
Contain major basic protein and eosinophil cationic protein
Characteristic appearance: Bilobed nucleus, large eosinophilic granules
Mast Cells
Tissue-resident cells
Release histamine, leukotrienes, prostaglandins
Important in allergic reactions
Characteristic appearance: Metachromatic granules
Granulomatous Inflammation
Granulomatous inflammation is a distinctive pattern of chronic inflammation characterized by focal collections of activated macrophages, often with epithelioid appearance, surrounded by lymphocytes.
Granuloma Formation
Initiation
Persistent antigen that resists phagocytosis
T cell activation and production of cytokines (IFN-γ, TNF)
Macrophage activation and aggregation
Maturation
Transformation of macrophages into epithelioid cells
Fusion of macrophages to form multinucleated giant cells
Surrounding rim of lymphocytes and fibroblasts
Resolution or Progression
Resolution: Removal of antigen, dissolution of granuloma
Progression: Continued antigen presence, fibrosis, calcification
Types of Granulomas
Foreign Body Granulomas
Formed in response to inert foreign material
Foreign material often visible within giant cells
Examples: Suture granulomas, talc granulomas
Immune Granulomas
Formed in response to poorly soluble particles that induce cell-mediated immunity
Examples:
Tuberculosis: Caseating granulomas
Sarcoidosis: Non-caseating granulomas
Crohn's disease: Non-caseating granulomas
Fungal infections: Suppurative granulomas
Diseases Associated with Granulomatous Inflammation
Infectious
Tuberculosis
Leprosy
Syphilis (tertiary)
Fungal infections (histoplasmosis, cryptococcosis)
Cat-scratch disease
Schistosomiasis
Non-infectious
Sarcoidosis
Crohn's disease
Foreign body reactions
Berylliosis
Primary biliary cholangitis
Systemic Effects of Inflammation
Inflammation, especially when severe or chronic, can produce systemic effects:
Acute Phase Response
Mediated by cytokines (IL-1, IL-6, TNF-α)
Characterized by:
Fever
Leukocytosis
Increased production of acute phase proteins
C-reactive protein (CRP)
Serum amyloid A (SAA)
Fibrinogen
Ferritin
Decreased production of albumin, transferrin
Fever
Regulated by hypothalamus
Induced by pyrogens:
Exogenous: Bacterial products (LPS)
Endogenous: IL-1, IL-6, TNF-α
Mechanism: Prostaglandin E2 production in hypothalamus
Adaptive value: Enhanced immune function, inhibition of microbial growth
Leukocytosis
Increased white blood cell count in blood
Patterns:
Neutrophilia: Bacterial infections, acute inflammation
Lymphocytosis: Viral infections, chronic inflammation
Eosinophilia: Allergic reactions, parasitic infections
Monocytosis: Chronic infections, inflammatory disorders
Cachexia
Profound weight loss and muscle wasting
Associated with chronic inflammatory diseases and cancer
Mediated by TNF-α (cachextin), IL-1, IL-6
Mechanisms:
Decreased appetite
Increased energy expenditure
Altered metabolism
Protein catabolism
Tissue Repair
Tissue repair is the restoration of tissue architecture and function after injury. It involves two distinct processes: regeneration and fibrosis (scarring).
Cell and Tissue Regeneration
Regeneration is the replacement of damaged cells by cells of the same type, restoring normal tissue structure and function.
Cell Proliferation
The capacity for regeneration depends on the proliferative ability of the tissue, which can be classified into three types:
Labile Cells
Continuously dividing cells
Rapid turnover
Examples: Epithelial cells of skin, gastrointestinal tract, genitourinary tract; hematopoietic cells
Stable Cells
Normally quiescent but can proliferate in response to injury
Examples: Hepatocytes, renal tubular cells, endothelial cells, fibroblasts, smooth muscle cells
Permanent Cells
Cannot undergo mitotic division in postnatal life
Examples: Neurons, cardiac myocytes, skeletal muscle cells (limited regeneration via satellite cells)
Cell Cycle
The cell cycle is the sequence of events that leads to cell division:
G0 Phase
Quiescent state
Cells not actively preparing to divide
G1 Phase
Cell growth and preparation for DNA synthesis
Restriction point: Decision to commit to division
S Phase
DNA synthesis
Chromosome duplication
G2 Phase
Preparation for mitosis
Cell growth continues
M Phase
Mitosis: Nuclear division
Cytokinesis: Cytoplasmic division
Regulation of Cell Proliferation
Cell proliferation is tightly regulated by:
Growth Factors
Epidermal growth factor (EGF): Epithelial cells
Platelet-derived growth factor (PDGF): Fibroblasts, smooth muscle cells
Fibroblast growth factor (FGF): Fibroblasts, endothelial cells
Vascular endothelial growth factor (VEGF): Endothelial cells
Transforming growth factor-β (TGF-β): Complex effects, often inhibitory
Cell Cycle Proteins
Cyclins and cyclin-dependent kinases (CDKs): Promote cell cycle progression
CDK inhibitors (p21, p27, p16): Inhibit cell cycle progression
Retinoblastoma protein (Rb): Regulates G1 to S transition
p53: "Guardian of the genome," arrests cell cycle in response to DNA damage
Extracellular Matrix (ECM) Interactions
Integrins: Transmit signals from ECM to cell
ECM components: Provide structural support and regulatory signals
Healing by Repair (Fibrosis)
When tissue damage is extensive or involves non-regenerative cells, healing occurs by replacement with connective tissue, leading to scar formation.
Phases of Wound Healing
Hemostasis (Immediate)
Vasoconstriction
Platelet aggregation and degranulation
Coagulation cascade activation
Formation of fibrin clot
Inflammation (1-3 days)
Neutrophil infiltration
Monocyte recruitment and transformation to macrophages
Phagocytosis of debris and bacteria
Release of growth factors and cytokines
Proliferation (3-14 days)
Angiogenesis: Formation of new blood vessels
Fibroplasia: Proliferation of fibroblasts
Collagen deposition
Epithelialization: Migration and proliferation of epithelial cells
Contraction: Mediated by myofibroblasts
Remodeling (14 days to 1 year or more)
Collagen reorganization
Decrease in vascularity
Increase in tensile strength
Scar maturation
Types of Wound Healing
Primary Intention (First Intention)
Clean, surgical incision with minimal tissue loss
Edges approximated by sutures
Minimal granulation tissue
Minimal contraction
Thin scar formation
Secondary Intention
Wound with significant tissue loss
Edges not approximated
Extensive granulation tissue
Significant contraction
Larger scar formation
Tertiary Intention (Delayed Primary Closure)
Initially left open, then closed surgically
Used for contaminated wounds
Allows for control of infection before closure
Combines features of primary and secondary healing
Factors Affecting Wound Healing
Local Factors
Infection: Prolongs inflammation, delays healing
Foreign bodies: Induce persistent inflammation
Blood supply: Adequate perfusion essential for healing
Mechanical factors: Tension, motion
Wound size and location
Radiation: Damages blood vessels, impairs healing
Systemic Factors
Age: Decreased healing capacity with aging
Nutrition: Protein, vitamin C, zinc deficiencies impair healing
Diabetes mellitus: Impaired angiogenesis, increased infection risk
Glucocorticoids: Inhibit inflammation and collagen synthesis
Smoking: Vasoconstriction, tissue hypoxia
Immunodeficiency: Increased infection risk, impaired healing
Pathologic Aspects of Repair
Excessive Repair
Hypertrophic Scars
Raised, red, firm scars
Confined to original wound boundaries
Excessive collagen deposition
May regress over time
Common in burns, wounds crossing flexor surfaces
Keloids
Raised, firm, irregular scars
Extend beyond original wound boundaries
Excessive collagen deposition
Do not regress
Genetic predisposition (more common in African Americans)
Tendency to recur after excision
Desmoplasia
Excessive fibrosis around tumors
May contribute to tumor progression
Examples: Pancreatic cancer, breast cancer
Deficient Repair
Dehiscence
Separation of wound edges
Often due to excessive tension or infection
Risk factors: Obesity, diabetes, steroid use, poor nutrition
Ulceration
Persistent defect in epithelial surface
Failure of re-epithelialization
Common in chronic wounds (pressure ulcers, diabetic ulcers)
Fibrosis in Specific Organs
Liver cirrhosis: Diffuse fibrosis disrupting normal architecture
Pulmonary fibrosis: Restrictive lung disease
Renal fibrosis: Progressive loss of renal function
Clinical Correlations
Inflammatory Diseases
Pneumonia
Acute inflammation of lung parenchyma
Causes: Bacteria, viruses, fungi
Patterns: Lobar, bronchopneumonia
Exudate: Fibrinous, suppurative
Resolution or organization (carnification)
Appendicitis
Acute inflammation of appendix
Initially neutrophilic infiltration
Progression to suppuration, gangrene, perforation
Complications: Peritonitis, abscess formation
Meningitis
Inflammation of meninges
Bacterial: Neutrophilic exudate
Viral: Lymphocytic exudate
Tuberculous: Granulomatous inflammation
Rheumatoid Arthritis
Chronic inflammatory disease of joints
Synovial inflammation, pannus formation
Joint destruction, deformity
Systemic manifestations: Rheumatoid nodules, vasculitis
Inflammatory Bowel Disease
Crohn's disease: Transmural inflammation, skip lesions, granulomas
Ulcerative colitis: Mucosal inflammation, continuous lesions, crypt abscesses
Wound Healing Disorders
Diabetic Foot Ulcers
Impaired healing due to neuropathy, vascular disease
Susceptibility to infection
Leading cause of non-traumatic amputations
Pressure Ulcers (Decubitus Ulcers)
Ischemic necrosis due to prolonged pressure
Common in immobilized patients
Staging based on depth of tissue involvement
Venous Stasis Ulcers
Due to venous hypertension, edema
Typically located on medial malleolus
Associated with varicose veins, post-thrombotic syndrome
Radiation-Induced Fibrosis
Late effect of radiation therapy
Progressive fibrosis of irradiated tissues
Vascular damage, tissue hypoxia
Summary of Key Concepts
Acute inflammation is a rapid response characterized by vascular changes, leukocyte recruitment, and chemical mediator release.
Leukocyte extravasation involves margination, adhesion, transmigration, and chemotaxis.
Phagocytosis is essential for elimination of microorganisms and involves recognition, engulfment, and killing.
Chemical mediators of inflammation include cell-derived (histamine, prostaglandins) and plasma-derived (complement, kinins) mediators.
Chronic inflammation is characterized by mononuclear cell infiltration, tissue destruction, and attempts at repair.
Granulomatous inflammation is a specific type of chronic inflammation characterized by epithelioid macrophages and giant cells.
Tissue repair involves regeneration (replacement with same cell type) and fibrosis (replacement with connective tissue).
Wound healing progresses through phases of hemostasis, inflammation, proliferation, and remodeling.
Factors affecting wound healing include local (infection, blood supply) and systemic (age, nutrition, diabetes) factors.
Pathologic aspects of repair include excessive repair (hypertrophic scars, keloids) and deficient repair (dehiscence, ulceration).
Practice Questions
A 45-year-old man presents with fever, productive cough, and right-sided chest pain. Chest X-ray shows consolidation of the right lower lobe. Sputum culture grows Streptococcus pneumoniae. Which of the following best describes the type of inflammatory exudate expected in this condition? A. Serous B. Fibrinous C. Suppurative D. Granulomatous E. Hemorrhagic
A 7-year-old boy has recurrent bacterial infections involving the skin, lungs, and lymph nodes. Laboratory studies show normal neutrophil count but impaired respiratory burst. Nitroblue tetrazolium test is negative. Which of the following is the most likely diagnosis? A. Leukocyte adhesion deficiency B. Chédiak-Higashi syndrome C. Chronic granulomatous disease D. Hyper-IgE syndrome E. Severe combined immunodeficiency
A 35-year-old woman undergoes excision of a benign breast mass. Six months later, she develops a raised, firm scar that extends beyond the boundaries of the original surgical incision. The lesion is pruritic and does not regress over time. Which of the following best describes this lesion? A. Hypertrophic scar B. Keloid C. Granulation tissue D. Desmoplasia E. Wound dehiscence
A 60-year-old man with a 30-year history of smoking presents with hemoptysis. Bronchoscopy reveals a mass in the right main bronchus. Biopsy shows squamous cell carcinoma. Microscopic examination of the tumor stroma reveals numerous fibroblasts and dense collagen deposition. Which of the following terms best describes this stromal reaction? A. Granulomatous inflammation B. Desmoplasia C. Keloid formation D. Wound contraction E. Metaplasia
A 25-year-old woman presents with fever, weight loss, and chronic diarrhea. Colonoscopy shows segmental areas of inflammation with deep, linear ulcers. Biopsy reveals transmural inflammation with non-caseating granulomas. Which of the following is the most likely diagnosis? A. Ulcerative colitis B. Crohn's disease C. Intestinal tuberculosis D. Diverticulitis E. Ischemic colitis
Answers:
B. Fibrinous. Lobar pneumonia caused by Streptococcus pneumoniae typically produces a fibrinous exudate in the alveolar spaces, leading to consolidation of the affected lobe.
C. Chronic granulomatous disease is characterized by defective NADPH oxidase activity, resulting in impaired respiratory burst and inability to kill catalase-positive organisms. The nitroblue tetrazolium test is negative because it relies on the respiratory burst to reduce the dye.
B. Keloid. Keloids are raised, firm scars that extend beyond the boundaries of the original wound. They do not regress over time and have a tendency to recur after excision. There is a genetic predisposition, with increased incidence in individuals of African descent.
B. Desmoplasia. Desmoplasia refers to the excessive production of fibrous connective tissue around a tumor. It is a common feature of many invasive carcinomas, particularly pancreatic and breast cancer.
B. Crohn's disease is characterized by transmural inflammation, skip lesions, and non-caseating granulomas. The presence of deep, linear ulcers and segmental involvement is characteristic of Crohn's disease, distinguishing it from ulcerative colitis, which typically shows continuous involvement limited to the mucosa.