Inflammation and Repair

Overview

• Inflammation: physiological response of vascularized tissues designed to deliver leukocytes and host defense molecules from the circulation to specifically targeted sites of infection or cell damage. Its primary purpose is to eliminate offending agents.

• Protective Nature: the term suggests a harmful reaction, inflammation is a critical, life-sustaining protective response. It serves two main functions:

  • To rid the host of the initial cause of cell injury (e.g., microbes or toxins).

  • To manage the consequences of such injury, including the removal of necrotic cells and tissues.

• Terminology: The suffix "-itis" appended to the name of an organ indicates inflammation at that specific site. Examples include:

  • Appendicitis: Inflammation of the appendix.

  • Conjunctivitis: Inflammation of the conjunctiva.

  • Pulpitis: Inflammation of the dental pulp.

  • Meningitis: Inflammation of the meninges.

Components of inflammatory response

• Major Participants: The inflammatory reaction primarily involves blood vessels and leukocytes.

  • blood vessels: dilate increase permeability enable circulating protein to enter site

• Leukocyte Components: Participants include various cells derived from hematopoietic stem cells in the bone marrow:

  • recruited activated to ingest destroy microbes and dead cells

    • Lymphocytes: These include $T$ cells and $B$ cells derived from lymphoid progenitors.

    • Monocytes: These transition into macrophages and dendritic cells in peripheral tissues.

    • Granulocytes: These include neutrophils, eosinophils, and basophils.

    • Mast Cells: Developed from mast cell progenitors.

• Inflammation and Repair:

  • Local Inflammation: Reactions are largely confined to the site of infection or damage, though they may produce systemic manifestations like fever (e.g., in bacterial or viral pharyngitis).

    • local tissue damage and symptoms - pain functional impairment

    • inflammatory reaction misdirected - autoimmune disease

  • Systemic Inflammation: Occurs in rare, severe situations such as sepsis.

• Mediators:

  • vascular and cellular reactions by soluble factors (cytokines, chemokines, complement) generated or activated in response to inflammatorys timulus

    • eg. microbes necrotic cells, hypoxia

Cardinal Signs of Inflammation

• Historical Perspective: The primary clinical manifestations of inflammation have been categorized over millennia.

• The Four Cardinal Signs :

  1. Rubor: Redness.

  2. Tumor: Swelling.

  3. Calor: Heat.

  4. Dolor: Pain.

• The Fifth Sign (Virchow, $19^{th}$ Century):

  5. Functio Laesa: Loss of function.

Inflammation and repair

• infection (bact, viral, fungal, parasitic and microbial toxins most common cause

• tissue necrosis: decreased blood flow, trauma, physical and chemical injury (thermal, burns frostbite, irradiation, exposure)

• foreign bodies: splinter dirt sutures, endogenous - urate crystal

• immune reactions: hypersensitivity

Sequential steps of inflam

• recognition of microbes and damage cells -PAMPS, DAMPs, cellular receptor, circulating proteins

  • cellular receptor for microbes: on plasma membrane and cytosol for intracellular

    • epithelial cells, macrophages, dendritic cells, leukocytes

  • recognition of microbes and damage cells

    • cytosolic receptors - NOD like receptors (NLR) recognize molecules from cell damage like DAMPS

      • part of the complement system, mannose binding lectin

    • include uric acid product of DNA breakdown and ATP

    • then recruits leukocytes and induce inflammation

• Acute inflammation

  1. Dilation of Small Vessels: Leads to a significant increase in blood flow.

     1. through inflammatory mediator histamine produced by mast cells, basophils (causes heat and redness)

  2. Increased Permeability: The microvasculature becomes "leaky," allowing plasma proteins and leukocytes to exit the circulation.

     1. lower blood flow, higher conc of RBC, stasis

     2. contraction of endothelial cells by histamine bradykinin, leukotrienes

  3. Emigration of Leukocytes: Leukocytes move from microcirculation, accumulate at the injury focus, and are activated to eliminate the offending agent.

     1. neutrophils and macrophages ingest and destroy bact

     2. macrophage also produce growth factor to aid in repair

     3. adhesion molecules and cytokines called chemokines

        1. in lumen: margination, rolling and adhesion to endothelium bind leukocytes

        2. migration across endothelium (transmigration or diapedesis)

        3. in tissues towards chemotactic stimulus

           1. exogenous factors: bacterial products (them)

           2. endogenous: “us” complement system

• Reaction of Blood Vessels:

  • Exudation: The process where fluid, proteins, and blood cells escape the vascular system into interstitial tissues or body cavities.

  • Edema: The result of exudation, localized swelling.

• Early Caliber Changes: Small vessel dilation is triggered by inflammatory mediators such as histamine, which is produced by mast cells and basophils. This vascular activity causes the heat and redness (erythema) observed at the affected site.

Lymphatics

• Role of Lymphatics: Lymph flow increases to drain edema fluid, leukocytes, cell debris, and potential microorganisms from the inflammatory site.

Mediators of Inflammation

• Neutrophuls predom in early inflam infiltrate

• more numerous, respond rapidly to chemokines, attach more firmly to adhesion molecules

• phagocytosis: leukocyte activation → phagocytosis and intracellular killing

  • recognition and attachment

  • engulfment: phagocytic vacuole

  • killing of microbe

• leukocytes do NOT distinguish between offender and host

• cell derived mediators: normally sequestered intracellular granule exocytosis or synthesized de novo: prostaglandins, leukotrienes, cytokines

• plasma derived mediators: complement produced in liver precursors that must be activated increase vascular permeability

Sequence of events in an inflammatory reaction

• recognition: of agent initiating stimulus for inflammation by cells with receptors to recognize microbial products and substances released from damaged cells

• recruitment of leukocytes and plasma prot

• removal: of stimulus for inflam by phagocytic cells ingest and destroy microbes and dead cells

• regulation: response is important for terminating reaction when accomplished purpose

• repair: healing damaged tissues

Acute inflammation: short term response of immune system to injury or infection

• redness, swelling, pain, heat, loss of function, purulent

• dilation small blood vessels and accumulation of leukocytes

• serous inflammation- exudate watery fluid outpour, large # of leukocytes

• purulent production of pus neutrophils, necrotic cells and edema

• ulcer: local defect, excavation of surface of an organ, shedding necrotic tissue

    outcomes:

• 1. Complete Resolution: Occurs when the injury is limited, short-lived, or involves minimal tissue destruction. Macrophages remove debris and microbes, lymphatics resorb edema fluid, and the tissue restores itself via regeneration.

• 2. Healing by Connective Tissue Replacement (Scarring/Fibrosis): This occurs when tissues are incapable of regeneration, there is substantial destruction, or abundant fibrin exudation cannot be cleared. The process of "organization" converts the area into a mass of fibrous tissue.

• 3. Progression to Chronic Inflammation: Happens when the acute response cannot be resolved due to the persistence of the injurious agent or interference with the healing process.

Chronic Inflammation

• Definition: A prolonged response (weeks to months) to some bact and pathogens difficult to eradicate, such as Tubercle bacilli.

  • more tissue destruction and scarring

  • prolonged (weeks or months), low grade insidious

  • causes:

    • persistent infection: difficult to eradicate bacteria -delayed type sensitivity →granulomatous

    • hypersensitivity disease: chronic inflam, excessive inappropriate activation of immune, against individual own tissue

    • prolonged exposure: potentially toxic agents exogenous or endogenous, silica → silicosis

• Morphologic Features:

  • Mononuclear Infiltration: Characterized by the presence of macrophages, lymphocytes, and plasma cells.

  • Tissue Destruction: Caused either by the persistent offending agent or by the inflammatory cells themselves.

  • Healing Attempts: Concurrent with damage, characterized by angiogenesis (proliferation of small blood vessels) and fibrosis.

• mediators

  • macrophages secrete cytokine and growth factors destroy foreign invaders activate T and B lymphocytes → chronic inflam

    • T cells + macrophages = granuloma, sometime assoc with necrosis

      • repair damage tissue

      • classically activated: macrophage induced by microbial products and cytokines (IFN) they phagocytose and destroy, potentiate inflam reaction

      • alternatively activated (1,3,4) macrophage induced by other cytokines in tissue repair and resolution of inflam

• granulomatous inflammation

  • foreign body: absence of t cell mediated immune response, often phagocytosis by macrophage - not immunogenic

  • immune granuloma: t cell mediated response, often microbe, Th1 → cytokine (IFN) activates macrophages

Tissue Repair

two processes:

• regeneration: restores normal cells

  • survive injury, retain capacity to proliferate

  • presence of tissue stem cells

  • hepatocytes epithelia of skin and intestine

    • labile: continuously dividing, lost and replaced by maturation from tissue stem cells (hemapoietic cells in bone marrow and epithelia skin)

    • stable: G0 stage, minimal proliferative activity (MAJORITY OF CELLS)

      • parenchyma of kidney, liver, pancreas

    • permanent tissues: terminal differentiated non prolif past postnatal life, neurons and cardiac muscle

• deposition: of connective tissues, scar formation

  • incapable of regeneration lays down fibrous connective tissue- provides stability

• Signals:

  • vascular endothelial cells and fibroblasts

Factors that influence tissues repair

• infection: prolong inflam, increase tissue injury ie. smoking

• diabetes: compromise tissues, decrease blood flow, decrease nutrients , alter inflam (sometimes overreacts)

• nutritional status: protein deficiency, vit C deficiency

• glucocorticoids: weakness of scar

• poor perfusion (peripheral vascular disease

• foreign bodies: impede healing perpetuates inflam

• Healing by First Intention: Also known as primary union. This applies to clean, uninfected surgical incisions where the edges are approximated by surgical sutures. It minimizes scarring.

  • Example: Surgical removal of a Squamous Papilloma

  • epithelial layer only

  • formation of blood clot → neutrophils at incision margin → basal cells increase mitotic activity → neutrophils replaced by macrophages, clear debris → neovasc reaches peak, granulation tissue fills space → collagen accumulation, fibroblast prolif → fibrous connective tissue devoid of inflam cells

• Healing by Second Intention: Occurs when there is extensive tissue loss. The wound is left open to heal from the bottom up.

  • avascular scar

  • primarily type I collagen

• Abnormality in tissue repair:

  • excessive formation of components of repair → hypertrophic scars and keloids - grows beyond boundaries or original wound and does not regress (more common in African Americans)