Inflammation and Repair II
Summary of Abbreviations
ARDS: Adult Respiratory Distress Syndrome
CNS: Central Nervous System
DIC: Disseminated Intravascular Coagulation
EGF: Epidermal Growth Factor
FGF: Fibroblast Growth Factor
HGF: Hepatocyte Growth Factor
IL: Interleukins
PDGF: Platelet-Derived Growth Factor
PMNs: Polymorphonuclear Neutrophils
SIRS: Systemic Inflammatory Response Syndrome
SLE: Systemic Lupus Erythematosus
TGF: Transforming Growth Factor
TNF: Tumor Necrosis Factor
VEGF: Vascular Endothelial Growth Factor
Second Line of Defense in Acute Inflammation
Lymphatics: These serve as the second line of defense in the acute inflammatory reaction when phagocytosis is insufficient to contain the injurious agent.
Lymphangitis: This refers to the inflammation of the lymphatic vessels. In this state, lymphatic channels are readily visible and inflamed, often manifesting as red streaks on the skin.
Reactive or Inflammatory Lymphadenitis: This is the inflammation of the lymph nodes.
Scope: Can be generalized throughout the body or limited to a few nodes near the site of infection.
Mechanism: Lymph nodes enlarge due to hyperplasia in lymph node follicles and an increase in the number of macrophages and lymphocytes.
Progression: If inflammation is not contained within lymphatic channels, it moves to draining lymph nodes (lymphadenitis). If still not contained, the agents may spill into the blood vessels, causing bacteremia.
Bacteremia: The presence of viable bacteria in the bloodstream.
Risks: Bacteria can deposit and cause secondary infections in the heart valves, meninges, kidneys, and joints.
Summary of Progression: Inflammation of lymphatic channels () \u2192 Spillage into draining lymph nodes () \u2192 Spillage into blood vessels ().
Outcomes of Acute Inflammation
Complete Resolution:
Restores the tissue to its normal state.
Occurs with mild injury and little tissue damage.
Common in skin-deep injuries, typically restricted to the epidermal layer or slightly below.
Healing by Scarring or Fibrosis:
Occurs when there is extensive tissue damage.
Applicable to tissues that cannot regenerate.
Involves abundant fibrin exudation and replacement by connective tissue.
Progression to Chronic Inflammation:
Occurs when the inflammatory reaction is not totally contained or the injurious agent persists.
Characterized by minimal or continuing inflammation/infection in the area.
Hereditary Defects Impairing the Acute Inflammatory Response
Deficiency of Complement Components:
Refers to immunodeficiency caused by the absence or suboptimal functioning of complement system proteins.
Results in increased susceptibility to infection, specifically with deficiencies in factors , , and .
Defects in Neutrophils:
Chronic Granulomatous Disease of Childhood:
An X-linked disorder.
Deficient activity of NADPH oxidase, which involves the transfer of electrons from NADPH to molecular oxygen to produce superoxide ().
Leads to the formation of granulomata in various tissues and organs.
Reactive Oxygen Species (ROS) Formation Process:
Superoxide is toxic to organisms and is converted to Hydrogen Peroxide () by superoxide dismutase.
is further converted by:
Catalase to Water and Oxygen.
Myeloperoxidase to Hypochlorite (toxic to humans in high concentrations).
Ferrous ion to the Hydroxyl radical (the most extremely reactive ROS).
Myeloperoxidase Deficiency: Sometimes associated with recurrent infections but often has little clinical consequence.
Chediak-Higashi Syndrome:
An autosomal recessive disorder.
Results in neutropenia, albinism, cranial and peripheral neuropathy, and a tendency for repeated infections.
Marked by the presence of abnormal white blood cells.
Morphological Patterns of Acute Inflammation
Serous Inflammation:
Characterized by the predominance of fluids (serum or secretions of mesothelial cells lining cavities like the peritoneal, pleural, and pericardial cavities).
Known as effusion when occurring in cavities.
Examples: Skin blisters, tuberculosis (TB) pleuritis.
Fibrinous Inflammation:
Involves a higher concentration of plasma proteins like fibrinogen and fibrin.
Presents as a thread-like or solid amorphous eosinophilic coagulum.
Examples: \"Bread and butter\" pericarditis, meningitis.
Suppurative or Purulent Inflammation:
Characterized by pus, which is a collection of liquified debris of necrotic cells, neutrophils, and edema fluid.
Caused by pyogenic (pus-producing) bacteria.
Abscess:
A localized collection of pus buried in a tissue, organ, or confined space.
Contains neutrophils, necrotic cells, and edema fluid.
Features a thick fibrous wall that can make it inaccessible to the circulation, often requiring surgical intervention rather than just antibiotics.
Ultimately replaced by connective tissue once the infection is contained.
Membranous Inflammation:
Involves necrosis of the mucosa and inflammatory exudate that remains attached as a surface membrane.
Examples: Diphtheria, membranous enterocolitis.
Clinical Distinction (\"Nice to Know\"): Diphtheric membranes are firmly attached; scraping them results in bleeding, whereas ordinary tonsillar abscess debris is easily detachable.
Ulcers:
A local defect or excavation of the surface of an organ produced by the sloughing of inflamed necrotic tissue.
Common in gastric/peptic sites or as stasis ulcers.
Characterized by PMN (polymorphonuclear neutrophil) infiltration and vascular dilatation in margins.
Chronic Inflammation
Common Causes:
Obesity, Diabetes, persistent infection, and injury.
Primary Pathways:
Persistent infection by intracellular microorganisms (e.g., TB, Treponema pallidum, viruses, fungi) leading to delayed hypersensitivity reactions and granulomas.
Prolonged exposure to non-degradable toxic substances (e.g., asbestosis, silicosis, atherosclerosis).
Autoimmunity: Immune reactions against one's own tissues (e.g., Rheumatoid arthritis, SLE).
Cellular Interactions:
Starts with T-lymphocyte stimulation.
Sensitized T-cells produce gamma interferon (\u1fe5-IFN), interleukins, and TNF.
These substances stimulate monocytes to differentiate into macrophages and activate existing macrophages.
Activated macrophages secrete potent antimicrobial substances (ROS, RNS, proteases) to destroy resistant pathogens.
Activated macrophages can also present antigens to B-cells for antibody production.
Cell Types Involved:
Lymphocytes: Smallest leukocyte with a dense nucleus and pale basophilic non-granular cytoplasm.
Eosinophils: Bilobed nucleus with large acidophilic granules; key in killing helminths/parasites and in allergic reactions.
Plasma Cells: Differentiated B-lymphocytes that secrete antibodies.
Giant Cells: Formed by the fusion of several macrophages in response to infection.
Fibroblasts: Responsible for synthesizing protein fibers (collagen, elastic, reticular) and ground substance.
Mononuclear Phagocyte System:
Maturation pathway: Bone marrow stem cell \u2192 Monoblast \u2192 Blood monocyte \u2192 Macrophage.
Tissue-specific names for resident macrophages:
Liver: Kupffer cells.
Lungs: Alveolar macrophages.
CNS: Microglial cells.
Bone: Osteoclasts.
Connective tissue: Histiocytes.
Macrophage Activation Pathways:
Classically Activated Macrophage (M1):
Induced by microbial products and cytokines like \u1fe5-IFN.
Produce ROS, NO, and lysosomal enzymes for microbicidal action.
Secrete IL-1, IL-12, IL-23, and chemokines to promote inflammation.
Alternatively Activated Macrophage (M2):
Induced by IL-4 and IL-13.
Produce growth factors and TGF-\u03b2 for tissue repair and fibrosis.
Secrete IL-10 and TGF-\u03b2 for anti-inflammatory effects.
Granulomatous Inflammation
Definition: A specialized type of chronic inflammation characterized by a collection of epithelioid cells surrounded by a rim of lymphocytes.
Types of Granulomas by Pathogenesis:
Foreign Body Granuloma: Occurs when an agent (e.g., talc, sutures, fibers) is too large for a single macrophage to phagocytose. No specific immune response is incited; nuclei of giant cells are haphazardly arranged.
Immune Granuloma: Caused by poorly degradable particulate inducing a cell-mediated immune response. Prototype is the tubercle.
Specialized Cells in Granulomas:
Epithelioid Cells: Activated macrophages with pale, eosinophilic cytoplasm and elongated nuclei (\"footprint\" shape); enhanced secretory and killing ability but decreased phagocytic ability.
Langhans Giant Cells: Formed by the fusion of epithelioid cells; nuclei are arranged at the periphery in a horseshoe pattern.
Touton Giant Cells: Union of foamy macrophages in fat necrotic tissues; nuclei are central, surrounded by peripheral fat vacuoles.
Morphological Patterns:
Caseating Granulomata: Center undergoes caseous necrosis (e.g., Tuberculosis).
Non-necrotizing Granulomata: No central necrosis (e.g., Sarcoidosis, Leprosy, Crohn\u2019s disease).
Suppurating Granulomata: Center shows suppurative necrosis with neutrophils (e.g., Cat Scratch Disease).
Systemic Effects of Inflammation (SIRS)
Fever: Caused by pyrogens acting on the thermoregulatory center in the hypothalamus.
Changes in Peripheral Blood:
Leukocytosis: Increase in total WBC count.
\"Shift to the Left\": Presence of many young/immature neutrophils.
Neutrophilia: Increase in neutrophils.
Absolute Lymphocytosis: Seen in Infectious Mononucleosis, mumps, and German measles.
Eosinophilia: Seen in bronchial asthma, hay fever, and parasitic infestations.
Leukopenia: Decreased WBC count, seen in typhoid, rickettsial, and viral infections.
Acute Phase Proteins: Increased levels of CRP (C-reactive protein), fibrinogen, and serum amyloid A protein (SAA).
Increased Erythrocyte Sedimentation Rate (ESR).
Increased Blood Coagulability: Leading to shock triad of DIC, hypoglycemia, and cardiovascular failure.
Tissue Renewal and Repair
Regeneration: Growth of cells/tissues to replace lost structures (restitution of normal structure).
Healing: A response to a wound, inflammatory process, or necrosis in organs incapable of regeneration. Involves a combination of regeneration and replacement by fibrous tissue (scar formation).
Proliferative Activity of Body Tissues:
Labile Tissues: Divide actively throughout life (e.g., epidermis, GI mucosa, bone marrow).
Stable (Quiescent) Tissues: Few divisions but can divide if activated (e.g., hepatocytes, renal tubular cells, smooth muscle, endothelium).
Permanent (Nondividing) Tissues: Incapable of regeneration (e.g., neurons, myocardial cells); always replaced by scar tissue (fibrosis or gliosis).
Growth Factors and Cytokines Summary:
EGF (Epidermal Growth Factor): Mitogenic for keratinocytes and fibroblasts.
TGF-\u03b1 (Transforming Growth Factor alpha): Stimulates replication of hepatocytes.
HGF (Hepatocyte Growth Factor): Increases cell motility and proliferation of epithelial/endothelial cells.
VEGF (Vascular Endothelial Growth Factor): Essential for angiogenesis; increases vascular permeability.
PDGF (Platelet-Derived Growth Factor): Chemotactic for PMNs/macrophages; stimulates wound contraction.
FGF (Fibroblast Growth Factor): Mitogenic for fibroblasts; stimulates keratinocyte migration and angiogenesis.
TGF-\u03b2 (Transforming Growth Factor beta): Major cytokine in fibrosis; stimulates TIMP (Tissue Inhibitor of Metalloproteinases) synthesis.
Types of Healing:
Healing by First Intention (Primary Union): Occurs in clean, incised wounds with good edge apposition (e.g., surgical wounds).
Healing by Second Intention (Secondary Union): Occurs in open wounds with significant tissue loss. Characterized by intense inflammation, abundant granulation tissue, and wound contraction.
Phases of Wound Healing:
24 Hours: Scab formation; neutrophils and clot formation.
Days 3-7: Granulation tissue formation (highly vascular newly formed connective tissue consisting of capillaries and fibroblasts).
End of 1 Month: Scar formation; high collagen produced by fibroblasts; decreased vascularization; progressive wound contraction.
Factors Delaying Repair:
Local: Retention of debris, impaired circulation, infection, mechanical stress.
Systemic: Deficiency of Vitamin C, amino acids, or zinc; excess glucocorticoids; debilitating diseases like Diabetes Mellitus.
Fibrosis: Excessive deposition of collagen and ECM induced by persistent injurious stimuli (e.g., chronic inflammation). TGF-\u03b2 is the major driver.
Questions & Discussion
Question: Describe gross findings of acute appendicitis.
Response: Swollen, erythematous, covered by yellowish exudate. Erythema is due to blood vessel dilation (). Swelling is edema (). Yellowish discoloration is due to suppurative reaction (pus).
Question: Which cell is noted first in acute inflammation?
Response: Neutrophils appear in the first hours. Monocytes replace them as the chronic phase begins ( days later).
Question: Which mediators cause pain ()?
Response: Prostaglandin and bradykinin.
Question: What cell is characteristic of a reaction to a suture ( nodule) after 3 months?
Response: Giant cell (foreign body giant cell formed by coalesced epithelioid cells).
Question: How does the body clear bacteria in pneumonia?
Response: Through oxygen-dependent microbial killing (oxidative burst), specifically utilizing hydrogen peroxide and the myeloperoxidase-halide system.
Question: What is indicated by an \"air-fluid level\" in a lung density on X-ray?
Response: Abscess formation. Liquefied necrosis results in a cavity where solid particles gravitate down and air remains above.
Question: Which process causes difficulty breathing in a patient with chronic silica dust exposure?
Response: Macrophage elaboration of cytokines leading to fibroblastic proliferation and interstitial fibrosis.
Question: How does the tensile strength of a surgical scar compare to normal skin?
Response: It reaches of normal tensile strength at 3 months post-operation.
Question: Which mediator produces shock in overwhelming infection?
Response: Nitric oxide, which acts as a powerful vasodilator in large amounts.
Question: Why is Mycobacterium tuberculosis difficult to destroy?
Response: Due to its lipid coat of mycolic acid, which resists neutrophil action and requires macrophage activation leading to granuloma formation.