Lec.2- Inflammation (Horn)

Inflammation: Overview

  • Inflammation is a vascular-type response involving changes in blood vessels at the site of injury or infection.
  • Triggers include infections, tissue damage, and inflammatory responses to normal processes (e.g., a stuffy nose) which are actually inflammatory proceeds.
  • Inflammation is primarily protective, recruiting host defenses (neutrophils, macrophages) and protective proteins to the offending agent.
  • Protective molecules are often proteins; the goal is defense and repair, but inflammation can be maladaptive, especially in chronic settings.
  • Inflammation is implicated in many diseases (e.g., arthritis, cancer, Alzheimer's disease); inflammation may contribute to disease progression rather than always being the direct cause.
  • Necrosis often accompanies inflammation because cell death releases intracellular contents that stimulate inflammation.
  • Today’s focus: acute vs chronic inflammation, with a look at mechanism, mediators, cells, patterns, and consequences.

Acute vs Chronic inflammation (overview and comparison)

  • Acute inflammation:
    • Onset: sudden; duration is short (rapid response, then subsides).
    • Major cellular mediators early on: neutrophils.
    • Tissue injury tends to be mild and limited due to the short duration.
    • Local signs are prominent.
  • Chronic inflammation:
    • Onset: slower to develop; lasts a long time; can be progressive.
    • Major cellular mediators later on: macrophages; lymphocytes may appear.
    • Tissue injury can be severe and progressive; repair attempts occur alongside ongoing inflammation.
    • If prolonged, symptoms can be persistent with ongoing tissue damage.
  • Inflammation is a protective mechanism, but chronic inflammation can contribute to tissue damage and disease progression.

The five cardinal signs and symptoms of acute inflammation

  • Heat (calor)
  • Redness (rubor)
  • Swelling (tumor)
  • Pain (dolor)
  • Loss of function (functio laesa)
  • Note: Ancient Greek origins explain these signs; Virchow added loss of function as a cardinal sign.
  • Latin terms (often tested): Calor, Rubor, Tumor, Dolor, Functio Laesa.
  • Inflammation signs result from vasodilation, increased vascular permeability, exudation, and leukocyte recruitment.

Offending agents that trigger inflammation

  • Infections: bacterial, viral, parasitic, fungal; prions are not infectious in the sense of this context.
  • Tissue necrosis or damage.
  • Foreign bodies: splinters, dirt, surgical devices, etc.
  • Endogenous harmful molecules: e.g., cholesterol crystals in atherosclerosis.
  • Immune reactions: allergies and hypersensitivities.
  • The presence of an offending agent activates the inflammatory response; recognition is the first essential step.

Recognition of offending agents: sentinels, receptors, and patterns

  • Sentinel cells in tissues:
    • Phagocytes (resident macrophages) and dendritic cells detect foreign material.
    • Mast cells are especially important in skin-associated inflammation.
  • Receptors:
    • Toll-like receptors (TLRs): recognize conserved microbial patterns and damage signals; there are several TLRs (e.g., a receptor recognizing double-stranded RNA indicates viral infection).
    • Phagocytic receptors on macrophages and neutrophils mediate attachment and uptake of microbes.
  • PAMPs and DAMPs:
    • PAMPs: pathogen-associated molecular patterns (e.g., dsRNA, bacterial lipopolysaccharide, CpG motifs in bacterial DNA).
    • DAMPs: damage-associated molecular patterns (ATP, extracellular potassium, extracellular DNA, etc.) released by necrotic cells.
  • Circulating patterns and tagging systems:
    • Complement system (a cascade of about 20 proteins) tags pathogens and damaged cells; activation leads to opsonization, chemotaxis, and membrane attack complex (MAC).
    • Mannose-binding lectins and collectins: tag bacteria by recognizing bacterial surface sugars; help recruit and activate immune components.
    • Antibodies (circulating proteins) tag offending agents for recognition by immune cells.
  • PAMPs, DAMPs, and circulating tagging systems drive the initiation and amplification of inflammation.

Mediators of inflammation: signals that ignite and regulate the response

  • Cytokines vs chemokines:
    • Cytokines: activate and coordinate immune cells; include TNF-α, IL-1, interferons, etc.
    • Chemokines: primarily chemoattractants that recruit leukocytes to the site; help cells migrate toward the offending agent.
  • Major mediators and their roles:
    • Histamine (a vasoactive amine): one of the earliest mediators released from mast cells; causes vasodilation and increased vascular permeability, contributing to heat, redness, and edema; also helps recruit leukocytes.
    • Lipid mediators derived from arachidonic acid:
    • Prostaglandins (via COX enzymes): vasodilation and modulation of permeability; contribute to pain and fever.
    • Thromboxanes: promote platelet aggregation and, in some contexts, vasoconstriction; also involved in hemostasis at injury sites.
    • Leukotrienes: increase vascular permeability and promote leukocyte recruitment; generally contribute to inflammation.
    • Prostacyclins: promote vasodilation and inhibit platelet aggregation (context-dependent).
    • Lipoxins: anti-inflammatory mediators that help terminate the inflammatory response.
    • Arachidonic acid metabolism: the first step is the action of cyclooxygenases (COX-1 and COX-2) on arachidonic acid to form prostaglandins and related products; NSAIDs inhibit COX enzymes to reduce inflammation.
    • Complement system mediators: C3a, C5a (anaphylatoxins) promote inflammation; C3b opsonizes pathogens; MAC (C5b-C9) can lyse microbes.
    • Interleukins and TNF family: IL-1, TNF-α promote fever, acute phase responses, and leukocyte recruitment/activation.
    • Chemokines and integrins: increase leukocyte adhesion and migration by modulating endothelial cell surface molecules and leukocyte integrins.
    • VEGF (vascular endothelial growth factor): promotes angiogenesis; signals endothelial cell migration and proliferation; important for new vessel growth but vessels are often leaky.
  • Kinetics and regulation:
    • Many mediators are short-lived; their production is localized to the site of inflammation.
    • Mediators can amplify each other in cascades (snowball effect via complement and other mediators).
    • Lipoxins and other anti-inflammatory mediators help shut down inflammation after the threat is controlled.

Early events: vascular changes and exudation

  • Primary effects of mediators on vessels:
    • Vasodilation: increased blood flow to the area, causing heat and redness.
    • Increased vascular permeability: spaces between endothelial cells widen, allowing exudate to escape into the tissue (edema) and proteins to leak out.
    • Endothelial cell retraction is the main mechanism for increased permeability; histamine is a key driver of this process.
  • Exudate vs transudate:
    • Exudate: protein-rich fluid with leukocytes; results from increased vascular permeability; contributes to edema and can contain cellular debris.
    • Transudate: fluid with low protein and few cells; occurs when there is increased hydrostatic pressure or decreased oncotic pressure rather than inflammation; eventually drained via lymphatics.
  • Edema and exudate:
    • Edema is the swelling from exudate accumulation.
    • If leukocytes enter the exudate, pus can form (purulent exudate).
    • Abscess formation is a localized collection of pus within tissue.
  • Time course:
    • Vascular changes and exudate formation occur rapidly and are typically transient (often ~
      15ext–30extminutes15 ext{–}30 ext{ minutes}
      ).

Leukocyte recruitment and activation: moving from blood to tissue

  • Stepwise leukocyte recruitment:
    • Rolling: selectins mediate initial loose arrest on endothelium.
    • Tight adhesion: integrins on leukocytes interact with endothelial adhesion molecules to stop rolling.
    • Transmigration (diapedesis): leukocytes squeeze between endothelial cells to enter tissue.
    • Chemotaxis: chemokines guide leukocytes toward the offending agent.
    • Integrin upregulation: leukocytes increase integrin activity to enhance adhesion and migration.
  • Leukocyte players and timing:
    • Neutrophils: first to arrive; short-lived; act as foot soldiers to contain the infection.
    • Macrophages: arrive later; longer-lasting; key players in chronic inflammation; phagocytose debris and microbes; secrete cytokines to recruit more leukocytes and activate immune responses.
    • Lymphocytes (B and T cells): appear during adaptive immunity; B cells produce antibodies; T cells can help activate macrophages and can directly kill infected/altered cells.
    • Eosinophils: increase in parasitic infections and allergic reactions; not primarily phagocytes; attack parasites from the outside and can damage surrounding tissue; elevated IgE correlates with eosinophilia.
  • Mast cells and other sentinels:
    • Mast cells release histamine and other mediators; they help kick off the inflammatory response.
  • Antigen presentation and adaptive activation:
    • Macrophages ingest microbes, degrade them, and present antigen fragments to T cells (antigen-presenting cells).
    • B and T lymphocytes are activated in response to presented antigens; B cells differentiate into memory cells and plasma cells (antibody-secreting).
    • Antibodies neutralize toxins, opsonize pathogens, and aid in pathogen destruction; memory B cells enable faster responses to future exposures.

Phagocytosis and intracellular killing mechanisms

  • Phagocytosis steps (by macrophages and neutrophils):
    • Recognition and attachment via phagocytic receptors.
    • Internalization to form a phagosome.
    • Fusion with a lysosome to form a phagolysosome where degradation occurs.
    • Destruction of microbes via digestive enzymes and reactive species.
  • Intracellular killing mechanisms:
    • Reactive oxygen species (ROS): produced by NADPH oxidase in the phagosome; examples include extO<em>2−∙ext{O}<em>2^{-\bullet}, extH</em>2extO2ext{H}</em>2 ext{O}_2, and extOH∙ext{OH}^{\bullet} (hydroxyl radical).
    • Reactive nitrogen species (RNS): nitric oxide (NO) generated by nitric oxide synthase (NOS); NO reacts with ROS to form potent radicals such as peroxynitrite.
    • Lysosomal enzymes: proteases, nucleases, lipases, etc., contained in the lysosome digest the engulfed material.
    • NADPH oxidase generates ROS to kill ingested microbes early in phagocytosis; NO and other reactive species contribute to microbial killing.
  • Special features:
    • Neutrophils can form neutrophil extracellular traps (NETs) by expelling DNA and antimicrobial proteins to trap and kill microbes, sacrificing themselves in the process.
  • Antigen processing by macrophages:
    • After digestion, macrophages display epitopes on their surface (antigen presentation); this activates T cells and helps tailor the immune response.
  • Special note on macrophages:
    • Macrophages can be resident in tissues or circulate as monocytes; monocytes differentiate into macrophages upon entering tissues.
    • Macrophages function as antigen-presenting cells (APCs) to activate adaptive immunity (B and T cells).
  • Cellular weapons vs tolerance:
    • While macrophages and neutrophils kill microbes, they must also regulate the response to prevent excessive tissue damage; anti-inflammatory mediators help quench inflammation.

Resolution and tissue repair after inflammation

  • Termination of inflammation:
    • Mediators are short-lived; degradation by enzymes (e.g., histaminase) reduces signaling.
    • Dilution and washout of mediators reduce their local concentrations.
    • Neutrophils undergo apoptosis; later stages involve anti-inflammatory mediators (e.g., lipoxins) to dampen the response.
  • Repair and regeneration:
    • If tissue can regenerate, restoration of normal architecture occurs.
    • If regeneration is limited, repair occurs via scar formation (fibrosis) with collagen deposition by fibroblasts.
    • In organs like the heart or brain, scarring can impair function; in other tissues, regeneration may be possible.
    • Fibroblasts secrete cytokines/chemokines and lay down extracellular matrix to form scar tissue.
  • Angiogenesis during healing:
    • VEGF signals the growth of new blood vessels to supply regenerating tissue.
    • Steps: separation from existing vessels by pericytes, endothelial cell migration and proliferation, tube formation, and remodeling.
    • New vessels are initially leaky, which can be detrimental in some contexts (e.g., neovascularization in the retina).
  • Regulating signals for healing:
    • VEGF is a key initiator for angiogenesis.
    • Enzymes and signals eventually stop new vessel formation as remodeling progresses.

Types of inflammation: serous, fibrinous, purulent, and more

  • Serous inflammation:
    • Fluid-rich exudate with few cells; relatively clear and protein-rich; commonly forms blisters (e.g., superficial burns).
  • Fibrinous inflammation:
    • Exudate has high protein content, especially fibrin; seen in linings of body cavities; fibrin plugs help to stabilize damaged areas.
  • Purulent inflammation (pus):
    • Pus is exudate containing numerous neutrophils, cellular debris, and microbes.
    • Abscess: localized collection of pus within tissue.
  • Clinical note on terminology:
    • When describing pus in clinical settings, use the term "purulent" (not colloquial spellings); e.g., purulent discharge.

Chronic inflammation and granulomatous inflammation

  • Chronic inflammation:
    • Dominated by macrophages and lymphocytes; tissue destruction and attempted repair occur simultaneously.
    • Triggers include persistent infections, autoimmune processes, long-term exposure to irritants (e.g., cholesterol crystals in atherosclerosis), and chronic hypersensitivity.
    • Macrophage activation leads to release of cytokines and growth factors, driving ongoing inflammation and tissue remodeling.
  • Macrophage polarization (two major types):
    • M1 (classically activated): pro-inflammatory; produce ROS/RNS; kill microbes; promote inflammation.
    • M2 (alternatively activated): anti-inflammatory and pro-repair; promote tissue remodeling and resolution of inflammation; regulate repair processes.
  • Lymphocytes and adaptive immunity in chronic inflammation:
    • B cells produce antibodies; may form memory cells for future encounters.
    • T cells activate macrophages and other immune cells; can directly kill infected or abnormal cells.
  • Eosinophils in chronic inflammation:
    • Elevated in parasitic infections and allergic diseases; release cytotoxic granules but can cause tissue damage to surrounding tissues.
  • Granulomatous inflammation:
    • A specific pattern where immune system walls off a persistent offending agent that cannot be eradicated.
    • Structure: aggregates of macrophages (including giant cells) and T lymphocytes; central necrosis may be present (caseous necrosis in TB and certain fungal infections).
    • Triggers include persistent infections (mycobacteria, certain fungi), foreign bodies (glass, splinters), and genetic defects affecting macrophage function.
  • Caseous necrosis within granulomas:
    • Often associated with tuberculous infections and certain fungal infections; characteristically cheesy appearance on histology.

Systemic manifestations of inflammation

  • Fever and pyrogens:
    • Pyrogens stimulate the hypothalamus to raise body temperature, producing fever.
  • Acute-phase response: acute-phase proteins in the blood
    • C-reactive protein (CRP)
    • Fibrinogen
    • Serum amyloid A
    • These proteins rise in response to inflammatory signals and can be used as clinical markers of inflammation.
  • Leukocytosis and leukocyte subset changes:
    • Leukocytosis: increased white blood cell count to meet inflammatory demands.
    • Neutrophilia: commonly associated with acute bacterial infections.
    • Eosinophilia: associated with parasitic infections or allergies.
    • Macrophage involvement in chronic inflammation may accompany shifts in leukocyte profiles.

Angiogenesis and remodeling in healing

  • VEGF-driven angiogenesis:
    • VEGF signals endothelial cells to separate from surrounding structures, migrate, and proliferate to form new vessels.
    • Pericyte recruitment stabilizes the new vessels; maturation follows with stopping signals for proliferation.
    • New vessels are often leaky early in formation, which can be detrimental in certain contexts (e.g., retina, diabetic retinopathy).
  • Implications for clinical contexts:
    • Anti-VEGF therapies are used to slow abnormal neovascularization in some diseases (e.g., certain retinal conditions).

Practical and exam-oriented notes

  • Inflammation is a balance between host defense and tissue injury; acute inflammation is a rapid, protective response dominated by neutrophils; chronic inflammation is prolonged, often macrophage- and lymphocyte-dominated with tissue remodeling and potential fibrosis.
  • Recognize the mediators and their primary roles: histamine (vascular changes), cytokines/chemokines (cell activation and recruitment), lipid mediators (COX products, lipoxins), complement, ROS/RNS, and growth factors (VEGF).
  • Know the patterns of exudates and when they occur: serous, fibrinous, purulent; abscess formation indicates localized pus collection.
  • Understand the phagocytosis pathway and antigen presentation: phagocytic uptake, formation of phagosome, lysosomal digestion, ROS/RNS killing, antigen presentation to T cells, and subsequent adaptive immune activation.
  • Grasp the switch from acute to chronic inflammation: persistent offending agent, immune dysregulation, and repair trying to occur concurrently, with macrophages central to chronic inflammation.
  • Remember key numerical/time references: acute vascular permeability and vasodilation are transient, often lasting about 15ext–30extminutes15 ext{–}30 ext{ minutes}; chronic processes can persist for days to years depending on tissue and context.

Quick reference: core terms and pathways (summary)

  • Offending agents: infections (bacteria, viruses, parasites, fungi), necrosis, foreign bodies, immune reactions, endogenous danger signals.
  • Sentinel recognition: phagocytes, dendritic cells; Toll-like receptors (TLRs); PAMPs; DAMPs.
  • Key mediators: histamine, cytokines (e.g., IL-1, TNF-α), chemokines, prostaglandins, thromboxanes, leukotrienes, prostacyclins, lipoxins, complement (C3a, C3b, C5a, MAC).
  • ROS/RNS: reactive oxygen species and reactive nitrogen species (e.g., O₂⁻, H₂O₂, OH•, NO, peroxynitrite).
  • Cellular players: neutrophils (acute); macrophages/monocytes (acute to chronic); lymphocytes (adaptive); eosinophils (parasites/allergies); mast cells (histamine release).
  • Outcome: attenuation of infection, tissue repair, scarring when regeneration is limited; granulomatous inflammation in persistent infections or foreign bodies.
  • Angiogenesis: VEGF-driven endothelial proliferation and vessel formation; later stabilization and stop signals; potential leaky vessels in newly formed tissue.