Understanding Inflammation

Concept of Inflammation

• Inflammation refers to the response of vascularized living tissue to injury.
• It aims to contain injury, destroy microorganisms, inactivate toxins, and prepare tissue for healing and repair.

General Features of Inflammation

• It involves a vascular wall response and an inflammatory cell response.
• Effects are mediated by circulating plasma proteins and factors from vessel walls or inflammatory cells.
• While mainly local, systemic effects like fever, leukocyte release, and liver acute phase responses can occur.
• Termination happens when the offending agent is eliminated, secreted mediators are removed, and anti-inflammatory mechanisms activate.
• Inflammation is closely tied to healing, initiating events that lead to tissue regeneration or fibrosis (scarring).
• While protective, inflammation can be harmful, causing hypersensitivity or organ damage such as in rheumatoid arthritis and atherosclerosis.
• Acute and chronic inflammations differ in onset time, cellular infiltrates, and systemic effects.

Causes of Inflammation

• Major causes include infections, immunologic reactions, tissue necrosis, and environmental substances.
• Different microorganisms (viruses, bacteria, fungi, parasites) trigger different inflammatory responses.
• Ischemia, trauma, and toxins can all result in tissue necrosis leading to inflammation.
• Immune reactions, including autoimmunity (against self) and allergies (against exogenous agents), lead to inflammation.

Signs of Inflammation

• The five classic clinical signs, most prominent in acute inflammation, are:
  • Warmth: Due to vascular dilation.
  • Erythema: Due to vascular dilation and congestion.
  • Edema: Due to increased vascular permeability.
  • Pain: Due to mediator release.
  • Loss of function: Due to pain, edema, tissue injury and/or scar.
• Redness results from vasodilation caused by histamine and prostaglandins as well as stasis of blood.
• Warmth results from increased blood flow.
• Swelling results from exudation of fluid triggered by increased vascular permability caused by histamine and prostaglandins.
• Pain results from the action of prostaglandins and kinins on sensory nerve endings.

Acute Inflammation

• Acute inflammation has three primary components:
  • Vascular dilation, which leads to increased blood flow.
  • Structural changes in the microvasculature, which allows plasma proteins and leukocytes to leave the circulation.
  • Leukocyte emigration from blood vessels, which leads to accumulation and activation at the injury site.

Reactions of Blood Vessels in Acute Inflammation

• These reactions involve changes in blood flow and vessel permeability.
• The reactions maximize the movement of plasma proteins and leukocytes to injury sites.

Changes in Vascular Flow and Caliber

• Vasodilation occurs by mediators like histamine acting on vascular smooth muscle.
• Increased blood flow results, causing heat and redness (erythema).
• Increased permeability follows vasodilation, leading to the outpouring of protein-rich fluid (exudate).
• Edema occurs due to excess fluid in interstitial tissue or body cavities and can be either exudates or transudates.
  • Exudates are inflammatory extravascular fluid with cellular debris and high protein concentration, reflecting increased vascular permeability.
  • Transudates are excess extravascular fluid with low protein content; they are an ultrafiltrate of blood plasma due to elevated fluid pressure or diminished plasma osmotic forces.
  • Pus is a purulent inflammatory exudate rich in neutrophils and cell debris.
• Fluid loss and vessel diameter increase lead to slower blood flow, concentrating red cells and increasing viscosity.
• These changes lead to stasis of blood flow, with small vessels engorged with red cells, seen as vascular congestion and localized redness.
• As stasis develops, blood leukocytes accumulate along the vascular endothelium.

Increased Vascular Permeability

• Increased permeability arises from retraction of endothelial cells and/or endothelial injury.

Responses of Lymphatic Vessels and Lymph Nodes

• Lymphatic flow increases to drain edema fluid, leukocytes, and cell debris from the extravascular area.
• Severe injuries lead to drainage that may transport the offending agent.
• Lymphatics may become inflamed (lymphangitis, appearing as red streaks) along with draining lymph nodes (lymphadenitis, with enlarged, painful nodes).
• Nodal enlargement is usually from lymphoid follicle and sinusoidal phagocyte hyperplasia.

Leukocyte Recruitment to Sites of Inflammation

• Leukocytes move in a multi-step process from the vessel lumen to the tissue interstitium.
• The process involves:
  • Margination, rolling, and leukocyte adhesion to the endothelium.
  • Transmigration across the endothelium.
  • Migration in interstitial tissues toward a chemotactic stimulus.
• Various cytokines (TNF, IL-1) promote selectin and integrin ligand expression, increasing integrin avidity.
• Tissue macrophages produce many of these cytokines.
• Neutrophils typically predominate early, later replaced by monocytes and macrophages.

Phagocytosis and Clearance of Offending Agents

• Recognition through receptors leads to leukocyte activation.
• Consequences of activation include enhanced phagocytosis, intracellular killing, and the release of cytokines, growth factors, and inflammatory mediators such as prostaglandins (PGs).
• Phagocytosis involves recognition/attachment, engulfment, and finally killing/degradation of ingested material.

Termination of Acute Inflammatory Response

• Inflammation declines due to the transient production and short half-lives of mediators.
• It is regulated by:
  • Switching from proinflammatory arachidonate metabolites (LTs) to anti-inflammatory lipoxins.
  • Production of anti-inflammatory cytokines like transforming growth factor-β (TGF-β) and IL-10.
  • Synthesis of resolvins and protectins derived from fatty acids.
  • Neural impulses that curtail macrophage TNF production.

Morphologic Patterns of Acute Inflammation

• Serous Inflammation: Marked by fluid transudates reflecting moderately increased permeable vessels; accumulations within cavities are called effusions, while accumulations elsewhere appear as burn blisters on skin.

• Fibrinous Inflammation: It has exudates with large fibrinogen amounts that convert to fibrin through coagulation and serosal surface involvement such as fibrinous pericarditis or pleuritis.

  • Fibrinous exudates may be resolved by fibrinolysis and macrophage clearance of debris, but larger exudates will convert to fibrous scar tissue by ingrowth of vessels and fibroblasts.

• Purulent (Suppurative) Inflammation and Abscess: Characterized by purulent exudates (pus) consisting of neutrophils, necrotic cells, and edema along with collections of purulent inflammation accompanied by liquefactive necrosis, usually in the setting of bacterial seeding.

  • These can seal off over time and organize into fibrous scar tissue

• Ulcers: Local erosions of epithelial surfaces which are generated by sloughing of inflamed necrotic tissue, with examples being gastric ulcers.

Outcomes of Acute Inflammation

• Influenced by injury, tissue involvement, and host responsiveness.
• Involves three potential general outcomes:
  • Complete resolution, with regeneration of native cells and restoration to normalcy.
  • Healing by connective tissue replacement (fibrosis), occurs if substantial tissue damage occurs and inflammation occurs in non-regenerating tissues, also in the setting of abundant fibrin exudation (called organization.
  • Progression to chronic inflammation.

Mediators of Inflammation

• Both vascular and cellular events are mediated by molecules from plasma or cells.
• Plasma-derived mediators synthesize in the liver and circulate as precursors.
• Cell-derived mediators are either preformed and released by granule exocytosis or synthesized de novo after a stimulus.
• Many mediators are short-lived and either degrade by enzymes, subdued by inhibitors, scavenged with antioxidants, or decay after a period of time.

Actions of Principal Mediators of Inflammation

• Vasoactive amines (histamine): Vasodilation and permeability alterations.
• Arachidonic acid metabolites (prostaglandins and leukotrienes): Multiple forms influencing vascular reactions and leukocyte chemotaxis. These are antagonized by lipoxins.
• Cytokines: Proteins produced by many cells that mediate multiple effects, mainly leukocyte recruitment and principal ones being TNF, IL-1, and chemokines.
• Complement System: Involves breakdown products responsible for:
  • Leukocyte chemotaxis
  • Opsonization/phagocytosis of microbes
  • Cell killing
• Kinins: Mediate vascular reaction and facilitate the occurrence of pain through proteolytic cleavage of precursors.