Inflammation Overview and Cardinal Signs

Inflammation is a vital physiological process that occurs in response to harmful stimuli such as pathogens, damaged cells, or irritants. This complex protective mechanism is characterized by a series of biological events, including the activation of various immune cells, blood vessels, and molecular mediators. The process not only helps to contain and eliminate the initial cause of cell injury but also plays a crucial role in initiating tissue repair and healing.

During inflammation, the body experiences several classic symptoms, which include redness (due to increased blood flow), heat, swelling (resulting from the accumulation of fluid and immune cells), pain (as a consequence of the release of inflammatory mediators), and loss of function in the affected area. These symptoms reflect the body's attempt to restore homeostasis and promote healing.

One of the key components of inflammation is the recruitment of phagocytic cells, such as neutrophils and macrophages, which work to engulf and destroy invading pathogens or dead cells. Additionally, plasma proteins, including antibodies and clotting factors, accumulate at the site of injury to facilitate the immune response and repair processes. Overall, while inflammation is essential for defending the body against threats, chronic inflammation can lead to tissue damage and contribute to a range of diseases, including autoimmune disorders, cardiovascular diseases, and cancer.

Overview

• Inflammation is a complex, multi-step reaction.
• It involves the accumulation of phagocytes and plasma proteins at sites of infection, toxin exposure, or tissue injury.
• Its purpose is to:
  • Isolate, destroy, or inactivate infectious microbes.
  • Remove tissue debris.
  • Promote tissue repair.

Cardinal Signs of Inflammation

• Rubor (Redness): Increased blood flow to the affected area.
• Tumor (Swelling): Increased capillary permeability and fluid accumulation.
• Calor (Heat): Increased temperature due to increased blood flow.
• Dolor (Pain): Altered or impaired function of the affected area.
• Functio laesa (Loss of Function): Impaired function of the affected area.

Steps in the Inflammatory Response

• Plasma-derived mediators: Released from the liver. Examples include acute-phase proteins, Factor XII (Hageman factor) activation, complement proteins, clotting/fibrinolytic system, and kinin system (

  • Bradykinin: Bradykinin is a potent vasoactive peptide that plays a critical role in the inflammatory response. It is formed from the cleavage of kininogen, a precursor protein, by the action of the enzyme kallikrein. Once released at the site of injury or inflammation, bradykinin acts on blood vessels to induce vasodilation, leading to increased blood flow and contributing to the cardinal sign of redness. Additionally, it enhances vascular permeability, allowing plasma proteins and leukocytes to migrate to the inflamed tissue, which facilitates the healing process. Furthermore, bradykinin is involved in pain signaling, as it sensitizes nerve endings and contributes to the sensation of pain (dolor). Its actions are transient and are modulated by various enzymes in the tissue that degrade bradykinin, ensuring a balanced inflammatory response.

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• Cell-derived mediators: Released from various cells. Examples include preformed mediators (histamine from mast cells, serotonin from platelets, lysosomal enzymes from neutrophils), and newly synthesized mediators (prostaglandins, leukotrienes, platelet-activating factor, nitric oxide, cytokines from various cells).

Defense by Tissue Macrophages

• Macrophages are present in tissues, providing initial protection against infection by phagocytizing invading microbes.

Localized Vasodilation

• Vasodilation of arterioles increases blood flow to the affected area.
• This process is primarily caused by histamine from mast cells and activated bradykinin.
• Mast cells are located in connective tissues, especially areas like lungs, skin, and gastrointestinal tract.
• Vasodilation results in redness and heat.

Increased Capillary Permeability

• Histamine and bradykinin increase the size of pores between endothelial cells.
• This leads to increased capillary permeability, allowing plasma proteins to move into tissue spaces.

Localized Edema

• Vasodilation and increased capillary permeability lead to localized edema.
• Increased blood flow increases capillary pressure (Pc).
• Escaped plasma proteins increase interstitial fluid colloid osmotic pressure (πi).
• Fluid moves from capillaries to the tissue.
• Edema symptoms include swelling and pain due to tissue distension.

Walling-Off the Inflamed Area

• Clotting and anti-clotting factors escape into the tissue space.
• Fibrinogen converts to fibrin, forming clots within the tissue.
• This effectively isolates the injured area and prevents the spread of infection.
• Anti-clotting factors later dissolve clots when no longer needed.

Infiltration of Phagocytes

• Increased numbers of phagocytes are needed to remove infectious microbes, debris, and prepare the injured area for healing.
• Neutrophils arrive first, typically within 1 hour.
• Monocytes arrive within 8–12 hours and transform into macrophages.
• Phagocytes emigration involves three steps: margination, diapedesis, and chemotaxis.

Opsonization

• Opsonization is the process of marking bacteria for phagocytosis.
• Opsonins, such as antibodies and complement protein C3b, bind to bacteria and mark them.
• The higher concentration of C3b is due to the increased permeability of capillaries and plasma protein leakage.
• C3b binds to bacteria and receptors on phagocytes, preventing bacterial escape.

Phagocytosis

• Phagocytosis is the process of ingestion and digestion of bacteria, foreign particles, and tissue debris.
• The phagocyte's plasma membrane engulfs substances in a process called endocytosis, forming an endocytic vesicle.
• The vesicle fuses with a lysosome (containing hydrolytic enzymes), forming a phagolysosome.
• The lysosomal enzymes degrade the engulfed material.
• Phagocytes, such as neutrophils and macrophages, engulf and destroy microbes.

Inflammatory Mediators

• Histamine and mast cells: Release histamine in response to various stimuli, leading to vasodilation, increased vascular permeability, and bronchoconstriction. Mast cells contain granules with other inflammatory mediators, including chemotactic factors for neutrophils and eosinophils, cytokines, prostaglandins, leukotrienes, and platelet-activating factor.
• Prostaglandins and leukotrienes: derived from arachidonic acid. Prostaglandins enhance inflammation, contract smooth muscle, increase capillary permeability, cause vasodilation, and act as pyrogens. Leukotrienes also enhance inflammation, increase vascular permeability, and cause vasodilation; they are bronchoconstrictors.
• Cytokines: small proteins produced by various cell types. Examples include interleukins (ILs), interferons (IFNs), and tumor necrosis factor-alpha (TNF-α).
• Chemokines: small peptides that act as chemotactic substances for immune cells.
• Nitric oxide (NO): produced by vascular endothelium. NO causes vasodilation and acts as a mediator of inflammation, inhibiting leukocyte aggregation, platelet adhesion, and cytokine release.

Fever

• Fever is a systemic response to inflammation or infection.
• Endogenous pyrogens (such as cytokines and prostaglandins) and exogenous pyrogens (bacteria and bacterial toxins) raise body temperature.
• Fever may impair the activity of infectious microorganisms or their toxins.

Anti-inflammatory Drugs

• In some cases inflammation can be inappropriate or exaggerated.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen, inhibit cyclooxygenase (COX) enzyme.
• This leads to reducing prostaglandin synthesis.
• Corticosteroids inhibit the release of arachidonic acid. This reduces inflammatory mediators.

This quiz covers the complex process of inflammation, detailing its purpose and the cardinal signs associated with it. Participants will learn about the roles of phagocytes, plasma proteins, and the stages of the inflammatory response. Test your knowledge on how these mechanisms work together to protect the body from injury and infection.