Premed · Premed · Immunology
Lecture 7: Inflammation: Acute and Chronic
Immunology
Learning Objectives
By the end of this lecture, students will be able to:
- Define inflammation and describe the cardinal signs of acute inflammation
- Explain the vascular and cellular events of the acute inflammatory response
- Describe the roles of key inflammatory mediators (cytokines, chemokines, lipid mediators, vasoactive amines)
- Distinguish between acute and chronic inflammation
- Explain the mechanisms of resolution of inflammation and tissue repair
Lecture Content
I. Overview of Inflammation
Inflammation is the body's protective response to infection, tissue injury, or noxious stimuli. Its purpose is to eliminate the cause of injury, clear damaged tissue, and initiate repair. The cardinal signs of inflammation, described by Celsus in the 1st century, are rubor (redness) due to increased blood flow from vasodilation, calor (heat) from increased blood flow and metabolic activity, tumor (swelling) from increased vascular permeability leading to fluid exudation, and dolor (pain) from stimulation of nerve endings by mediators such as bradykinin and prostaglandins. A fifth sign, functio laesa (loss of function), was added by Virchow and results from pain and swelling. While inflammation is beneficial when it eliminates pathogens, it can also be harmful when it causes tissue damage or progresses to chronic disease.
II. Acute Inflammation -- Vascular Events
The vascular response to tissue injury unfolds in a characteristic sequence. Transient vasoconstriction lasting seconds is mediated by neurogenic reflexes in arterioles. This is quickly followed by vasodilation, occurring within minutes and mediated by histamine, nitric oxide (NO), and prostaglandins (PGI2, PGE2). Vasodilation increases blood flow to the area, producing redness and warmth, and first affects arterioles before spreading to capillary beds. Increased vascular permeability follows, as endothelial cell contraction creates gaps between cells. This process is mediated by histamine, bradykinin, leukotrienes (LTC4, LTD4, LTE4), C3a, and C5a, and allows protein-rich fluid (exudate) containing complement, antibodies, and acute-phase proteins to move from plasma into tissue spaces, causing edema. As fluid leaves the vasculature, stasis develops -- blood flow slows, red blood cells become more concentrated (hemoconcentration), and leukocytes begin to marginate along vessel walls.
III. Acute Inflammation -- Cellular Events (Leukocyte Recruitment)
Leukocyte extravasation follows a well-characterized multi-step adhesion cascade. During margination and rolling, leukocytes move to the vessel periphery due to stasis, where selectin-mediated interactions create weak, transient adhesion that causes leukocytes to "roll" along the endothelium. E-selectin and P-selectin on the endothelium (and platelets) bind sialyl-Lewis X on leukocytes, while L-selectin on leukocytes binds GlyCAM-1 and CD34 on the endothelium. During activation, chemokines displayed on the endothelial surface bind leukocyte chemokine receptors -- IL-8 (CXCL8) is a major neutrophil chemoattractant -- triggering a conformational change in leukocyte integrins to a high-affinity state. Firm adhesion then occurs as activated integrins (LFA-1, Mac-1, VLA-4) bind their endothelial ligands (ICAM-1, VCAM-1), arresting leukocytes on the endothelium. Transmigration (diapedesis) follows as leukocytes squeeze between endothelial cells (paracellular movement mediated by PECAM-1/CD31) or pass through endothelial cells (transcellular movement), crossing the basement membrane with the help of matrix metalloproteinases (MMPs). Finally, chemotaxis guides leukocytes along chemotactic gradients toward the site of infection or injury, following chemoattractants such as C5a, LTB4, bacterial fMLP, and chemokines like IL-8.
Neutrophils are the first cells recruited, arriving within hours and predominating in acute inflammation. Monocytes arrive later, at 24-48 hours, and differentiate into macrophages at the site of inflammation.
<image>A step-by-step illustration of the leukocyte adhesion cascade in a postcapillary venule. The vessel lumen is shown at top with blood flow from left to right. Step 1: Rolling -- neutrophils loosely tethered to endothelium via selectin-carbohydrate interactions (P-selectin and E-selectin on endothelium binding sialyl-Lewis X on the neutrophil). Step 2: Activation -- chemokines (IL-8) displayed on the endothelial surface bind CXCR1/2 on the neutrophil, triggering integrin activation (shown as conformational change from bent to extended form). Step 3: Firm adhesion -- activated LFA-1 and Mac-1 integrins on the neutrophil bind ICAM-1 on the endothelium. Step 4: Transmigration -- neutrophil squeezing between two endothelial cells via PECAM-1 interactions, crossing the basement membrane. Step 5: Chemotaxis -- neutrophil following a gradient of chemoattractants (C5a, fMLP, LTB4) toward bacteria at the tissue site of infection.</image>
IV. Chemical Mediators of Inflammation
A complex array of chemical mediators orchestrates the inflammatory response. Vasoactive amines include histamine, released from mast cells, basophils, and platelets, which causes vasodilation and increased permeability via H1 receptors on endothelium, and serotonin, released from platelets, which has vasoactive effects. Plasma proteases include the complement system (C3a and C5a as anaphylatoxins, C3b as opsonin, and MAC for lysis), the kinin system (bradykinin causes vasodilation, pain, and increased permeability), and the coagulation/fibrinolytic system (thrombin, fibrin, and plasmin).
Arachidonic acid metabolites (eicosanoids) are released from membrane phospholipids by phospholipase A2 and follow two main enzymatic pathways. The cyclooxygenase (COX) pathway produces PGE2 (vasodilation, pain, fever), PGI2 or prostacyclin (vasodilation, inhibition of platelet aggregation), and TXA2 or thromboxane A2 (vasoconstriction, platelet aggregation). COX-1 is constitutively expressed while COX-2 is inducible by inflammation, and both are targets of NSAIDs. The lipoxygenase pathway produces LTB4 (a potent neutrophil chemoattractant) and the cysteinyl leukotrienes LTC4, LTD4, and LTE4, which cause bronchospasm and increased vascular permeability and were historically known as the slow-reacting substances of anaphylaxis. Lipoxins, also derived from arachidonic acid, are anti-inflammatory and promote the resolution of inflammation.
Cytokines are central mediators of inflammation. TNF-α, produced by macrophages, activates endothelium, causes fever, drives the acute-phase response, and at high levels can cause septic shock. IL-1 has similar effects including fever, endothelial activation, and acute-phase protein induction. IL-6 drives the acute-phase response, activates B cells, and causes fever. IL-8 (CXCL8) is the major chemokine for neutrophil chemotaxis, and IL-12 activates NK cells and promotes Th1 differentiation. Platelet-activating factor (PAF) is a lipid mediator that promotes platelet aggregation, vasodilation, increased permeability, and leukocyte activation. Reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radical, are produced by NADPH oxidase in phagocytes during the respiratory burst and kill microbes but also cause tissue damage. Nitric oxide (NO), produced by iNOS in macrophages, causes vasodilation and has microbicidal and anti-inflammatory properties at low concentrations.
V. Systemic Effects of Acute Inflammation
When inflammation is sufficiently intense, systemic effects develop. Fever occurs when pyrogenic cytokines (IL-1, TNF-α, IL-6) act on the hypothalamus, inducing PGE2 production and raising the thermoregulatory set point. Fever enhances immune function and inhibits some pathogen growth. The acute-phase response involves the liver producing acute-phase proteins in response to IL-6, IL-1, and TNF-α. These include C-reactive protein (CRP), which acts as an opsonin and activates classical complement; serum amyloid A (SAA); fibrinogen, whose elevation leads to increased erythrocyte sedimentation rate (ESR); mannose-binding lectin (MBL); and hepcidin, which sequesters iron. Meanwhile, the negative acute-phase proteins albumin and transferrin decrease. Leukocytosis results from accelerated release of white blood cells from bone marrow, driven by G-CSF and GM-CSF, and a "left shift" -- increased immature neutrophils (bands) in the blood -- may be observed. In extreme cases, sepsis and septic shock develop from overwhelming cytokine release (a cytokine storm), leading to hypotension, disseminated intravascular coagulation (DIC), and multi-organ failure.
<image>A flowchart showing the systemic effects of acute inflammation. At the top, activated macrophages at a tissue infection site release TNF-alpha, IL-1, and IL-6 into the bloodstream. Three downstream pathways are shown: (1) TNF-alpha and IL-1 act on the hypothalamus to induce fever via PGE2; (2) IL-6 acts on the liver (hepatocytes) to stimulate production of acute-phase proteins (CRP, fibrinogen, SAA, MBL, hepcidin), with CRP and MBL shown returning to the infection site for opsonization and complement activation; (3) TNF-alpha and G-CSF act on bone marrow to stimulate leukocytosis and mobilization of neutrophils into the bloodstream. A warning box at the bottom shows that excessive systemic TNF-alpha release leads to septic shock: vasodilation, hypotension, DIC, and multi-organ failure.</image>
VI. Chronic Inflammation
Chronic inflammation is a prolonged inflammatory response lasting weeks to months or even years. It is characterized by infiltration with mononuclear cells (macrophages, lymphocytes, and plasma cells), simultaneous tissue destruction and repair, and fibrosis with angiogenesis. Causes include persistent infections (tuberculosis, hepatitis viruses, fungi), prolonged exposure to toxic agents (silica, asbestos), autoimmune diseases (rheumatoid arthritis, SLE, inflammatory bowel disease), and obesity, which produces chronic low-grade inflammation.
A specialized form of chronic inflammation is granulomatous inflammation. A granuloma is an organized collection of activated macrophages (known as epithelioid cells) and multinucleated giant cells, surrounded by lymphocytes and fibroblasts. Granulomas may be caseating, with central necrosis as seen in tuberculosis, or non-caseating, without central necrosis as seen in sarcoidosis. They form when macrophages cannot eliminate a pathogen, such as Mycobacterium tuberculosis, and are maintained by Th1 cytokines, particularly IFN-γ and TNF-α.
VII. Resolution of Inflammation and Tissue Repair
Resolution is the return to normal tissue homeostasis and requires elimination of the inciting stimulus, cessation of mediator production, apoptosis of neutrophils followed by their clearance by macrophages (a process called efferocytosis), and a phenotype switch in macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory and pro-repair). Critically, resolution is an active process driven by pro-resolving mediators including lipoxins (from arachidonic acid), resolvins (from omega-3 fatty acids EPA and DHA), and protectins and maresins. Anti-inflammatory cytokines such as IL-10 and TGF-β further dampen the response.
Tissue repair proceeds through one of two mechanisms. Regeneration replaces damaged cells with the same cell type, as occurs with hepatocytes and epithelial cells. When regeneration is not possible, fibrosis or scarring replaces the damaged tissue with connective tissue, involving fibroblast proliferation, collagen deposition, and angiogenesis.
