9&10: Inflammation: Causes, Types, and Cardinal Signs

• Inflammation is a mechanism of disease, alongside adaptive tissue responses, vascular disturbances, cell degeneration and necrosis, healing and repair, neoplasia, and teratology.
• Inflammation's five cardinal signs are heat, redness, swelling, pain, and loss of function.
• Acute inflammation lasts from seconds to 2-3 days and involves vascular changes with neutrophils.
• Subacute inflammation lasts from 2-3 days to around 2 weeks.
• Chronic inflammation lasts from weeks to months, involving cellular changes with lymphocytes and macrophages.
• Inflammation and repair are intertwined; determining whether they are beneficial or harmful depends on the context.

Causes of Inflammation

• Infections like bacterial, viral, parasitic, or fungal infections
• Tissue necrosis from ischemia, trauma, or physical/chemical injury
• Foreign bodies trigger inflammation
• Immune reactions, including autoimmune diseases and reactions against environmental substances or microbes, play a role

Acute Inflammation Overview

• Key aspects are vascular changes and cellular changes
• Involves soluble mediators as well as terminology and examples

Vascular Changes

• Fundamental to acute inflammatory reactions
• Reactive components are present in blood
• Involves changes in blood flow and vascular permeability

6 Key Points of Vascular Changes

• Fleeting vasoconstriction occurs transiently
• Arteriolar dilation
• Increased permeability
• Increased hydrostatic pressure
• Loss of laminar flow
• Margination and leukocyte migration

Sequence of Vascular Changes

• Brief vasoconstriction occurs in seconds due to adrenergic or neurogenic factors
• Vasodilation (arteriolar dilation) happens, leading to open capillary beds and causing redness (erythema) and heat

Permeability of Vessels

• Fluid enters the interstitial space
• Blood in the vessel becomes more viscous, slowing outflow
• Exudation occurs in 10-30 minutes

Fluid Escape into Interstitial Space

• Initial fluid escape results in transudate, characterized by low protein levels (<30 g/L) and low cell count (<1,500 cells/mL)
• Over time with increased vascular permeability and white blood cell margination, the fluid becomes an exudate (pus) with high protein levels (>30g/L) and high cell count (>1,500 cells/mL)

Triple Response

• A patch of injured skin produces a sequential triad
• Immediate local reddening due to vasodilation (active hyperaemia)
• Surrounding red flare response due to chemical mediators stimulating local free nerve endings
• Weal response includes local swelling due to cytokines increasing local vascular permeability

Endothelial Cell Effects

• Damage to cells results in acute cell swelling
• Endothelial damage can slow blood flow and lead to hypoxia
• Increased vascular permeability

Plasma Proteins Role in Interstitium

• Complement proteins are needed to initiate MAC/opsonisation if required
• Albumin transports Ca, Cu, Zn (+ many drugs) & ceruloplasmin transports Cu
• Transferrin transports Fe & has antibacterial/antiviral properties
• Haptoglobin binds free haemoglobin
• Immunoglobulins aid in binding to antigen & fixing complement
• Fibrinogen contributes to haemostasis

Vascular Changes Sequence Continued

• Increased inflow and normal outflow leads to increased IV hydrostatic pressure
• Fluid moves into the interstitium
• Laminar blood flow is lost, and white cells marginate

Endothelial Cell Contraction

• Is induced by histamine, bradykinin, and leukotrienes
• Is rapid and short-lived, lasting 15-30 minutes

Endothelial Injury

• Is caused by burns, irradiation, UV damage, and some bacterial toxins
• Mild injury results in vascular leakage continued for 2-12 hours

Margination and Migration of White Cells

• Process is promoted by soluble mediators and the expression of adhesion molecules by white blood cells and endothelial cells which include selectins, integrins and Ig
• Chemoattractants such as plasminogen and proteolytic enzymes involved

Leukocyte Margination and Migration

• Vascular changes promote these processes mostly in the post-capillary venule
• Migration across the endothelium is aided by a lower surface charge and shear force in venules, which allows for cell adhesion and migration

Leukocyte Migration and Chemotaxis

• At the site of injury, leukocytes migrate directionally (chemotaxis) guided by chemoattractants
• Extrinsic chemoattractants include bacteria and viruses.
• Intrinsic chemoattractants are complement peptides, collagen, cell membrane fragments, eicosanoids and kallikrein.

Cellular Changes - Neutrophils

• Neutrophils are the first line of phagocytes, equipped with potent cytoplasmic enzymes
• They exhibit a metabolic burst that is oxygen-dependent (superoxides, peroxide, and myeloperoxidases) via free radicals, also oxygen-independent systems like lactic acid, cationic proteins, and lactoferrin for intracellular killing
• Degranulation releases bactericidal lysosomal enzymes that is tissue and neutrophil toxic
• Neutrophil extracellular traps (NETs) are formed to trap pathogens

Neutrophil Extracellular Traps (NETs)

• Visualized in cytospins of septic synovial and peritoneal fluid samples (horses) using immunofluorescence

Cellular Changes - Macrophages

• Macrophages are derived from blood monocytes and migrate to tissue injury sites within 24-48 hours
• Macrophages phagocytose dead cells, bacteria, and tissue debris for antigen processing and presentation to T lymphocytes (CD4)
• They migrate more slowly than neutrophils but can survive for months and proliferate in situ
• Macrophages are active against fungi and protozoa
• Fixed tissue macrophages (dendritic cells) reside in organs, lymphoid tissue and skin
• Kupffer and Langerhan are fixed tissue macrophages

Macrophages - Cytokines

• Produce pro-inflammatory cytokines IL-1, TNF-a, and IL-12, and also the anti-inflammatory cytokine IL-10
• Macrophages morph into "epithelioid macrophages" with chronic stimulation and IFN-γ, displaying uniform, rounded cells, abundant cytoplasm, developed secretory function, and decreased phagocytic ability
• May fuse to form multinucleate giant cells

Phagocytosis

• The process involves opsonins such as Fc fragment of IgG, C3b and collectins
• Opsonins bind to complementary receptors like FcyR and CR1 to trigger engulfment
• This leads to phagosome and phagolysosome formation and degranulation

Macrophage Activation

• Classically activated macrophages (M1) and alternatively activated macrophages (M2) exist
• M1 are activated by microbes and IFN-γ, producing ROS, NO, and lysosomal enzymes for microbicidal actions, phagocytosis, and killing of bacteria/fungi, causing inflammation
• M2 are activated by IL-13 and IL-4, promoting growth factors and TGF-β for tissue repair and fibrosis, resulting in anti-inflammatory effects.

Eosinophils

• Involved in allergic and parasitic inflammatory responses
• Cytoplasmic granules include
  • Major Basic Protein (MBP) causing histamine release from mast cells
  • Histaminase
  • Eosinophil cationic protein (ECP) kills parasites
  • Collagenases cause tissue damage
  • Peroxidases

Eosinophils Release

• Eosinophils respond to histamine released from mast cells but can either stimulate or inhibit mast cell degranulation through histaminases
• Have minor phagocytic activity; amplify inflammation through leukotrienes

Basophils and Mast Cells

• Basophils are blood-borne granulocytes originating from bone marrow
• Mast cells are replicative cells derived from undifferentiated mesenchymal cells around blood vessels
• Both types are motile and have receptors for the Fc portion of IgE
• They readily degranulate when antigens bind to cell-bound IgE molecules

Basophils and Mast Cells - Vasoactive Substances

• These substances are released during trauma or insect bites
  • Heparin causes thrombosis and blood stasis
  • Histamine increases vascular permeability and acts as a chemoattractant for neutrophils and eosinophils
  • Leukotrienes increase vascular permeability and cause smooth muscle contraction
• Acute inflammation leads to permeability changes and edema formation

Platelets

• Platelets are anucleate cells derived from megakaryocytes in the bone marrow which accumulate in vessels at inflammatory sites
• They are activated by ADP, collagen, or thrombin, leading to adhesion, shape change (via vWF) to bind collagen
• Secretion (ADP, 5HT, proteases, TXA-2) attracts chemoattractants and increases blood vessel permeability
• Aggregation (fibrinogen) leads to thrombus formation and augmentation of the inflammatory process

Lymphocytes Role

• Mediate Humoral (Ab) and cell mediated immunity (CMI)
• APCs process and present antigens to naive T lymphocytes, activating them
• Activated T lymphocytes (CD4 helper) orchestrate adaptive immune response if it is required
• Lymphocytes, particularly T lymphocytes, are more important during chronic inflammation

Lymphocytes

• T lymphocytes: antigen-specific helper and cytotoxic (CD8) & helper/suppressor (CD4) subtypes
• B lymphocytes produce antibodies specific to an Ag
• B lymphocytes that produce specific antibodies appear morphologically different = plasma cells, important in Chronic inflammation