Inflammation: Types, Causes, and Host Response

• Inflammation serves as a host response to local injury in vascularized tissues that are infected or damaged
• Inflammation brings cells and molecules of host defense from the circulation to eliminate the offending agents
• Inflammation is not in itself a disease, but usually a manifestation of disease
• Inflammation terminates when the offending agent is eliminated

Stimuli of Inflammation

• Infections caused by bacteria, viruses, or fungi can lead to inflammation
• Trauma, whether blunt or penetrating, can induce an inflammatory response
• Physical and chemical agents, such as irradiation, burns, and acids, may trigger inflammation
• Tissue necrosis can act as a stimulus for inflammation
• Foreign bodies, such as sutures, can initiate an inflammatory reaction
• Immune reactions are known to contribute to inflammation

Classification of Inflammation

• Inflammation is classified into acute and chronic forms
• Acute inflammation is the initial and often transient tissue reaction to injury
• Chronic inflammation represents subsequent and often prolonged tissue reactions following the initial response
• The classification is characterized by differences in the cell types participating in the inflammatory response

Acute Inflammation (AI)

• Acute inflammation is an rapid initial response to infections or tissue damage
• Acute inflammation develops within minutes to hours
• Acute inflammation has a short duration, lasting several hours to a few days
• Exudation of fluid and plasma proteins (oedema) occurs during acute inflammation
• Emigration of leukocytes (neutrophils) is a key feature of acute inflammation
• Failure to clear the stimulus in acute inflammation can lead to chronic inflammation (CI)

Chronic Inflammation

• It is of longer duration than acute inflammation
• Chronic inflammation is associated with more tissue destruction
• The presence of lymphocytes and macrophages characterizes chronic inflammation
• Proliferation of blood vessels occurs during chronic inflammation
• Deposition of connective tissue is a feature of chronic inflammation

Features of Acute and Chronic Inflammation

Cardinal Signs of Inflammation

• Rubor (Redness)
• Tumor (Swelling)
• Calor (Heat)
• Dolor (Pain)
• Functio laesa (Loss of function)

Components of Acute & Chronic Inflammation

• The major participants in acute and chronic inflammation include blood vessels and leukocytes
• Blood vessels dilate, slowing down blood flow and increase permeability
• Characteristics of the endothelium lining change, causing leukocytes to migrate into the tissues
• Leukocytes are activated to ingest and destroy microbes and dead cells

Sequence of Events in Inflammation

• Recognition of the offending agent by host cells in the extravascular tissue
• Recruitment of leukocytes and plasma proteins into the tissue
• Elimination of the stimulus for inflammation
• Regulation of the response
• Repair of damaged tissue

Acute Inflammation

• Involves vascular changes
• Includes cellular events (leukocytes)

Vascular Changes

• Vasodilation is induced by mediators like histamine on vascular smooth muscle
• Vasodilation is one of the earliest manifestations of acute inflammation
• It involves the arterioles initially and then leads to the opening of new capillary beds
• Vasodilation increases blood flow, resulting in heat and redness (erythema)

Increased Permeability of the Microvasculature

• Contraction of endothelial cells: increased interendothelial spaces result
• An outpouring of protein-rich fluid into the extravascular tissues occur

Vascular Changes: Stasis

• Stasis involves slower blood flow, concentration of red cells, and increased blood viscosity
• Engorgement of small vessels
• Vascular congestion & localized redness occurs
• Neutrophils accumulate along the vascular endothelium
• Endothelial cells are activated by mediators and express increased levels of adhesion molecules

Vascular Events in Acute Inflammation

• Acute inflammation involves vascular events such as exudate and transudate formation

Characteristics of Leaked Fluid (Exudation)

• It is the escape of fluid, proteins, and blood cells from blood into tissue or body cavities
• An exudate is an extravascular fluid with high protein concentration and cellular debris
• A transduate is fluid with low protein content, little or no cellular material, and low specific gravity
• Oedema indicates an excess of fluid in the interstitial tissue or serous cavities and can be an exudate or transduate
• Pus is a purulent exudate containing leukocytes, dead cells, and microbes

Characteristics of Oedema

Cellular Events in Acute Inflammation

• Involves the recruitment of Leukocytes to sites of infection and injury
• In the lumen, margination, rolling, & adhesion to endothelium
• Transmigration across the endothelium (diapedesis)
• Migration in interstitial tissues toward a chemotactic stimulus

Mechanism of Margination

• White blood cells are confined to a central axial column of the vessel
• Due to stasis, hemodynamic conditions change, and more white cells assume a peripheral position along the endothelial surface

Rolling and Adhesion

• Leukocytes tumble slowly along the endothelium and adhere transiently (rolling)
• Leukocytes eventually come to rest and adhere firmly (adhesion)

Diapedesis

• Leukocytes insert pseudopods into the interendothelial junctions & squeeze through to assume a position between the endothelial cell & the basement membrane
• Leukocytes traverse the basement membrane & escape into the extravascular space

Morphologic Patterns of Acute Inflammation

• Morphologic hallmarks: Dilation of small blood vessels & accumulation of leukocytes and fluid in the extravascular tissue.
• Special morphologic patterns are often superimposed: Severity of the reaction, Specific cause, Particular tissue and site involved
• Provide valuable clues about the underlying cause

Serous Inflammation

• Exudation of cell-poor fluid into spaces created by cell injury or body cavities lined
• Increased vascular permeability or secretions of mesothelial cells
• Example: Skin blister from a burn

Fibrinous Inflammation

• Vascular leaks are large and/or there is a local pro-coagulant stimulus (e.g. cancer cells)
• Fibrinogen leaks & Fibrin is formed
• Characteristic inflammation lining body cavities e.g. pericardium
• Leads to scarring - organisation

Purulent (Suppurative) Inflammation

• An exudate of neutrophils, liquefied debris of necrotic cells, and edema fluid (pus) is formed
• Bacterial infection (pyogenic)-staphylococci
• Produced by seeding of pyogenic bacteria
• Acute appendicitis

Ulcers

• They consist of a local defect on the surface of an organ
• Production occurs by the shedding of inflamed necrotic tissue
• Peptic ulcer
• Chronic ulcers: Fibroblasts, scarring, and inflammatory cells

Outcomes of Acute Inflammation

• Complete resolution due to little tissue destruction & removal of microbes
• Healing by scarring, or fibrosis in tissue incapable of regeneration
• Chronic inflammation results from persistence of an agent or disturbance in healing

Mediators of Inflammation

• Substances that initiate & regulate inflammatory reactions reactions
• Important categories include vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and complement activation
• Secreted by cells, or generated from plasma proteins
• The major cell types are sentinels that detect invaders and tissue damage
• Plasma-derived mediators are produced in the liver

Chronic Inflammation

• A response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations
• May follow an episode of acute AI
• Starts insidiously as a low-grade, smoldering response

Causes of Chronic Inflammation

• Persistent infections, e.g., Mycobacteria
• Hypersensitivity diseases: excessive activation of the immune system/ unregulated immune responses against microbes or common environmental substances
• Prolonged exposure to potentially toxic agents, e.g., silicosis
• Sometimes, it takes a specific pattern - granulomatous reaction –Fibrosis may dominate in the late stages

Morphology of Chronic Inflammation

• Infiltration with mononuclear cells, encompassing macrophages, lymphocytes, & plasma cells
• Accompanied by tissue destruction
• Attempts at healing by connective tissue replacement of damaged tissue (angiogenesis & fibrosis)

Granulomatous Inflammation

• Granulomatous inflammation involves collections of activated macrophages/epithelioid cells
• Epithelioid cells & multinucleated giant cells
• Foreign body granulomas (talc)
• Immune granulomas (cytokines e.g. IL2

Morphology of Granulomatous Inflammation

• Aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes
• In Mycobacterium tuberculosis a combination of hypoxia and free radical–mediated injury leads to a central zone of necrosis
• Grossly, caseous necrosis has a granular, cheesy appearance
• Microscopically, caseous granulomas appear as amorphous structureless, eosinophilic, granular debris, with complete loss of cellular details

Differential of Granulomatous Inflammation

• Limited number of conditions that cause it (some life-threatening)
• TB granuloma, referred to as a tubercle
• Leprosy
• Syphilis
• Disease of Unknown aetiology- Sarcoidosis
• Crohn disease

Systemic Effects of Inflammation

• Inflammation is associated with cytokine-induced systemic reactions collectively called the acute-phase response
  • Fever
  • Acute-phase proteins (C-Reactive Protein)
  • Leukocytosis
• Other effects include increased pulse and BP, shivering, chills, anorexia, somnolence, and malaise, likely due to cytokine actions on brain cells

Fever

• An elevation in body temperature by 1° to 4°C
• Substances that induce fever are called pyrogens
• Fever is mediated by prostaglandins in the hypothalamus
• NSAIDs can inhibit prostaglandin synthesis

Acute Phase Proteins

• Mostly synthesized in the liver
• Increase plasma concentrations several hundred-fold
• Three of the best-known proteins
  • C-reactive protein (CRP)
  • Fibrinogen
  • Serum amyloid A (SAA) protein

Leukocytosis

• Leukocyte count ++ 15,000 /20,000 cells/mL > 100,000 cells/mL.
• Most bacterial infections = increase neutrophil count: neutrophilia
• Viral infections = increase in lymphocytes: lymphocytosis
• In some allergies and parasitic infestations = increase in eosinophils: eosinophilia
• Certain infections are associated with a decreased number of circulating white cells leukopenia

Systemic Effects of Inflammation

• Disseminated Intravascular Coagulation (DIC)
• Hypotensive shock
• Metabolic disturbances (including insulin resistance and hyperglycemia)
• This triad is known as septic shock