Leukocyte Recruitment Mechanisms

Inflammation Overview

• Inflammation is a Latin word, "inflammatio", meaning "setting on fire"
• It is a protective response to eliminate the cause of injury or necrotic cells
• The process neutralizes harmful agents and initiates healing
• Inflammation can be acute or chronic

Learning Objectives

• Describe the general features and mechanisms of inflammation
• Describe the role of principal mediators in inflammation
• Describe vascular and cellular events associated with inflammation
• Distinguish between acute and chronic inflammation

Hallmarks of Acute Inflammation

• Redness
• Heat (increased temperature)
• Swelling (edema)
• Pain
• Loss of function

The Pillars of Inflammation

• Described by Aulus Cornelius Celsus (over 2000 years ago)
• Include: redness, swelling, heat, pain, loss of function

Inflammation: Friend or Foe?

• Inflammation is a protective response to injury and/or necrotic cells
• Inflammation can cause harm to healthy tissue

Mediators of Inflammation

• Produced locally or circulating in plasma as inactive precursors activated at the site of inflammation
• Induce effects by binding target cells (except ROS and some proteases)
• Prime targets for anti-inflammatory drugs

Major Players in Inflammation

• Mast cells
• Macrophages
• Platelets
• Lymphocytes
• Monocytes
• Polymorphonuclear leukocytes
• Plasma proteins
• Fibroblasts
• Complement
• Clotting factors/kininogens

Chemical Mediators of Inflammation

• Produced locally within cells at the site of inflammation, or within the plasma
• May include histamine, serotonin, prostaglandins, leukotrienes, platelet-activating factor (PAF), reactive oxygen species(ROS), nitric oxide, and Cytokines

Mediator Summaries

• Histamine: increased vascular permeability, vasodilation
• Serotonin: increased vascular permeability, vasodilation
• Prostaglandins: vasodilation, pain, fever
• Leukotrienes: increased vascular permeability, chemotaxis, leukocyte adhesion/activation
• Platelet-activating factor(PAF): vasodilation, increased vascular permeability, leukocyte activation, etc.
• Reactive oxygen species (ROS): killing of microbes
• Nitric oxide: vasodilation, reduced leukocyte adhesion
• Cytokines: Local endothelial activation, chemotaxis, leukocyte activation, systemic effects.

Cytokines

• Polypeptides/small proteins released from cells to interact with and communicate with each other
• Types of cytokines includes lymphokines(lymphocyte produced), monokines (monocyte produced), chemokines (chemotactic activities), interleukins, and interferons.
• Cytokines involved in systemic inflammation are tumor necrosis factors.

Cytokine Signaling

• Autocrine: Cell signals itself
• Paracrine: Cell signals neighboring cell
• Endocrine: Cell signals distant cell through blood circulation

Inflammasome

• Cytosolic multiprotein complex
• Activates inflammatory responses
• Promotes maturation and secretion of pro-inflammatory cytokines (IL-1 and IL-18)

T-Helper Cells and Regulation

• Pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-23, TNF-α by Th17) mediate inflammation
• Regulated by anti-inflammatory cytokines produced by regulatory T cells (e.g., IL-10, TGF-β).

Acute Phase Response

• Non-specific indicators of inflammation
• Systemic effects of inflammation
• Production of acute-phase proteins (e.g., fibrinogen and CRP), etc.
• Symptoms include fever, anorexia, malaise, somnolence, and leukocytosis.
• Includes factors that cause shock such as high TNF & IL-1, DIC (disseminated intravascular coagulation)
• Results in high levels of acute-phase proteins (like CRP) and increased production of leukocytes in the bone marrow

Acute Phase Proteins (APPs)

• Large group of biochemically and functionally unrelated proteins
• Plasma concentrations increase or decrease in response to tissue injury, acute infections, burns or chronic inflammation
• Examples include CRP, serum amyloid protein

Wound Healing and Tissue Repair

• Tissue repair = regeneration (complete functional replacement) or resolution
• Tissue repair depends on cell proliferation, extracellular growth factors and ECM (extracellular matrix)`

Cell Proliferation

• Labile tissues – continuously dividing (e.g., hematopoietic cells, GI tract epithelia)
• Stable tissues – quiescent but can proliferate (e.g. liver, pancreas)
• Permanent tissues – terminally differentiated and non-proliferative (e.g. neurons, cardiac muscle cells)

Extracellular Growth Factors

• Signaling molecules that stimulate cell proliferation, movement, and differentiation
• Types of growth factors include platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-B).

Extracellular Matrix (ECM)

• Complex network that surrounds cells
• ECM sequesters water, provides mechanical stability, a substrate for cell adhesion.
• Provides a scaffolding structure for tissue renewal
• Acts as a reservoir of growth factors

Tissue Repair: Wound Healing

• Healing can occur via first intention or second intention
• In first-intention healing, there is only minimal injury or damage
• Second-intention healing occurs when there is more extensive damage

Granulation Tissue

• Composed of inflammatory cells and fibroblasts
• Granulation tissue forms during wound healing, and is composed of blood vessels

Chronic Inflammation

• Lasting weeks, months or years
• Characterized by tissue damage
• Involves continuous activation of macrophages, angiogenesis, and fibrosis

Systemic effects of inflammation

• Describes fever, malaise, or other non-specific indicators that might indicate inflammation
• Non-specific markers of inflammation include ESR (Erythrocyte Sedimentation Rate).

Leukocyte-induced tissue injury

• Caused by ROS, RNS, enzymes that act on surrounding tissues not just solely on the original invaders
• Occurs in autoimmune diseases, allergic reaction, and other conditions.

Clinical examples of inflammation

• Includes respiratory, transplant, glomerulonephritis、septic sock, and vasculitis; arthritis, atherosclerosis, transplant rejection, and pulmonary fibrosis; acute and chronic inflammation

Fibrosis

• Excessive scarring exceeding typical wound healing
• Can also be a normal healing response (such as with a wound) or occur as a pathologic response (disease)

Inflamed Capillary Bed

• Shows increased blood flow within capillaries
• Shows leakage of plasma proteins as edema occurs
• Shows migration and accumulation of leukocytes at the site of the injury