Acute and Chronic Inflammation

ACEM Primary, Pathology Level 1

Overview: Why Inflammation Matters in Emergency Medicine

• Inflammation is the fundamental pathophysiological process underpinning the majority of critical presentations seen in the ED: sepsis, ARDS, anaphylaxis, trauma-induced coagulopathy, and multi-organ failure.
• Understanding the cellular and molecular machinery of both acute and chronic inflammation allows the emergency physician to predict disease trajectories, interpret biomarkers, and understand the mechanism of action of anti-inflammatory therapeutics.

The Inflammatory Response: Fundamental Concepts

Inflammation is a coordinated host defence response to tissue injury, infection, or immunological insult. It involves two major arms:

• Innate immunity: rapid, non-specific, pattern-recognition based
• Adaptive immunity: slower, antigen-specific, mediated by lymphocytes

In the ED context, it is predominantly the innate inflammatory response that drives acute deterioration in conditions such as sepsis, SIRS, and ALI/ARDS.

Cellular Mediators

Key Cell Types

Neutrophil Activation: A Three-Stage Process

Neutrophil activation is central to the innate inflammatory response and occurs in three sequential stages:

1. Margination: neutrophils adhere to capillary endothelium via ICAM-1 and selectins (upregulated by IL-8, PAF, C5a), then migrate into the interstitial space
2. Priming: stimulated by GM-CSF, IFN-γ, and IL-3; neutrophils generate preformed mediators and lysosomal contents
3. Stimulation: triggered by IL-1, IL-8, TNF-α, complement C5a, PAF, LTB₄, and LPS; results in release of damaging mediators

In the lung, inappropriate stimulation causes lysosomal contents to be released directly onto the endothelium, a critical mechanism in ARDS.

Chemical Mediators

Cytokines

• Cytokines are low molecular weight proteins (up to 80 kDa) produced by activated leukocytes, fibroblasts, and endothelial cells.
• They act on surface receptors of target cells, ultimately influencing protein synthesis.

Pro-inflammatory Cytokines

Anti-inflammatory Cytokines

The Time Course of Cytokine Release in Sepsis

• An early pro-inflammatory surge (TNF-α, IL-1β) is rapidly followed by release of pro-inflammatory blockers (IL-1 receptor antagonist) and anti-inflammatory cytokines (IL-10).
• This biphasic response explains why patients may initially survive the cytokine storm but later die from immunosuppression and secondary infection.

ED Pearl: IL-6 concentrations rise within 30-60 minutes of major injury/surgery, peak at ~24 hours, and remain elevated 48-72 hours. CRP lags behind IL-6 (reflecting hepatic synthesis time). In sepsis, IL-6 and IL-10 levels correlate with mortality risk in some studies.

Lipid Mediators

The Acute-Phase Response

Stimulated primarily by IL-6 (and to a lesser extent IL-1), the liver produces acute-phase proteins:

• C-reactive protein (CRP): non-specific opsonin; augments phagocytosis; lags behind IL-6
• Fibrinogen: coagulation; elevated in sepsis, driving hypercoagulable state
• α₂-macroglobulin and other antiproteinases: limit protease-mediated tissue damage

The acute-phase response also drives fever (pyrexia), leukocytosis, and neuroendocrine changes (HPA axis activation).

Cytokine Receptors and Regulation

Cytokine signalling is highly regulated:

• Multi-subunit receptors: e.g. IL-2 receptor has α, β, and γ subunits; all three required for high-affinity binding and full signal transduction
• Receptor type variation: IL-1 receptor type I preferentially binds IL-1α; type II preferentially binds IL-1β
• Ligand passing: TNF binds transiently to receptor type I (full signal transduction), then moves to type II receptor (triggering apoptosis)
• Soluble receptors: shed from cell surfaces or enzymatically cleaved; generally compete with membrane-bound receptors to dampen cytokine effects (e.g. sTNF-R limits TNF-α activity in sepsis). Exception: soluble IL-6 receptor acts as an agonist
• Receptor antagonists: IL-1ra binds IL-1 receptors without triggering signalling; elevated in sepsis as part of endogenous regulation

T-Cell Subsets and Adaptive Immunity

• In the ED, Th1/Th17 dominance is relevant in autoimmune presentations, while Th2 dominance underpins anaphylaxis and severe asthma.
• In sepsis, the balance between pro- and anti-inflammatory T-cell subsets determines the degree of immunosuppression.

Neutrophil-Mediated Tissue Damage: Four Mechanisms

Four groups of substances released from activated neutrophils drive organ injury (particularly in ARDS):

1. Cytokines (TNF-α, IL-1β), activate endothelium; upregulate ICAM-1 and selectins; positive feedback on further neutrophil recruitment
2. Protease enzymes: elastase (nonspecific: cleaves collagen, fibrinogen, elastin); matrix metalloproteinases (more substrate-specific)
3. Reactive oxygen species: OH•, O₂⁻, H₂O₂; direct endothelial damage
4. Lipid mediators: LTB₄ (neutrophil chemotaxis); PAF (permeability, platelet activation)

Acute vs Chronic Inflammation: Key Differences

Chronic Inflammation Mechanisms

• In chronic inflammation, Th1 and Th17 cells activate macrophages that release IL-1 and TNF-α, which in turn trigger chemokines and further inflammatory cytokines.
• TGF-β from neutrophils and Treg cells drives fibroblast stimulation, leading to fibrosis.
• In rheumatoid arthritis, TNF-α appears to be the predominant driver; in autoinflammatory diseases (e.g. gout), IL-1 is the key mediator.

Genetic Factors in Inflammatory Response

Polymorphisms in cytokine genes can significantly alter inflammatory responses and outcomes:

• Homozygotes for the TNFB2 allele have higher TNF-α levels and increased mortality from sepsis
• Polymorphisms in the IL-1RA gene are associated with raised IL-1RA concentrations in sepsis
• The IL-10 gene (chromosome 1q31) has a functional dinucleotide repeat polymorphism in the promoter region, relationship with levels in sepsis is not fully established

These findings explain interpatient variability in sepsis outcomes and may eventually guide personalised immunomodulatory therapy.

Emergency Medicine Relevance

Sepsis and the Cytokine Cascade

• The biphasic inflammatory response in sepsis, early pro-inflammatory surge followed by immunosuppression, directly informs ED management.
• Targeting a single cytokine (e.g. anti-TNF-α antibodies) has failed in human sepsis trials despite success in primate models, due to the profound redundancy and synergy of cytokine networks.
• This supports the current approach of source control, antibiotics, and supportive resuscitation rather than immunomodulation.

Biomarkers

• CRP lags behind the tissue injury/infection event due to IL-6-mediated hepatic synthesis; a rising CRP >24h after initial presentation may indicate evolving sepsis or complication
• IL-6 rises within 30-60 minutes of major tissue insult, understanding this time course helps interpret inflammatory markers in trauma patients
• Lactate remains more immediately useful for resuscitation endpoints, but CRP and procalcitonin guide antibiotic stewardship

ARDS

• Neutrophil-mediated endothelial damage via ROS, proteases, and cytokines is the pathological basis of ARDS.
• Understanding this mechanism supports lung-protective ventilation strategies aimed at minimising further inflammatory injury (ventilator-induced lung injury).
• IL-8 drives neutrophil recruitment into the lung, a key step in ALI progression.

Anaphylaxis

• Mast cell degranulation releasing histamine, PGD₂, LTB₄, TNF-α, and IL-4 drives the acute phase.
• The late phase (hours later) involves eosinophil-mediated damage via cysteinyl leukotrienes, eosinophil cationic protein, and major basic protein, the mechanism underlying biphasic anaphylaxis.
• This is why observation periods after adrenaline administration are clinically justified.

Allergic Asthma: Biphasic Response

• The early phase involves IgE-mediated mast cell degranulation → bronchospasm (minutes).
• The late phase (hours) involves Th2 lymphocyte and eosinophil infiltration, sustained airway inflammation, and structural remodelling.
• Glucocorticoids work primarily by inhibiting the Th2-driven cytokine environment (IL-4, IL-5, IL-13) responsible for the late phase.

Anti-inflammatory Drug Targets in the ED

Key Takeaway for Viva

Be prepared to explain:

1. The sequential cellular events from tissue injury → cytokine release → organ damage
2. Why sepsis treatment does not target single cytokines (redundancy, synergy, timing)
3. The difference between acute (neutrophil-dominated) and chronic (macrophage/lymphocyte-dominated) inflammation
4. How the biphasic response applies clinically in anaphylaxis and asthma