Pathogenesis of Compensatory Anti-Inflammatory Response Syndrome (CARS)
CARS represents a global deactivation of the immune system that occurs as a counter-regulatory mechanism to limit excessive inflammation, characterized by immune cell reprogramming, altered leukocyte function, and increased susceptibility to secondary infections. 1, 2
Core Pathophysiologic Mechanism
CARS develops as the body's attempt to restore homeostasis after an initial pro-inflammatory insult (SIRS), but when this compensatory response becomes excessive, it creates a state of functional immunosuppression 1, 3. The syndrome is not simply immune suppression but rather represents a compartmentalized reprogramming of immune cells where circulating leukocytes show altered function while tissue-resident leukocytes remain primed or activated 3.
Cellular and Molecular Mechanisms
Immune Cell Activation and Cytokine Production
Anti-inflammatory cytokines are produced simultaneously with pro-inflammatory mediators, not sequentially as originally thought 4, 2. When tissue injury occurs (surgical trauma, infection, severe inflammation), macrophages, neutrophils, endothelial cells, and fibroblasts become activated 4.
The balance between pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8) and anti-inflammatory cytokines (primarily IL-10) determines clinical outcome 4, 2. IL-10 levels correlate exponentially with IL-6 levels, and this relationship intensifies with sepsis severity 5.
Greater sepsis severity produces a disproportionate elevation of anti-inflammatory responses relative to pro-inflammatory responses, creating a dysbalanced immune state 5. This exponential correlation appears to be a function of TLR (Toll-like receptor) signaling intensity 5.
Mixed Antagonist Response Syndrome (MARS)
A critical nuance: early sepsis and severe inflammatory states are characterized by concomitant SIRS and CARS (termed MARS), not sequential phases 5. This simultaneous activation of both pro- and anti-inflammatory pathways occurs through:
- Autocrine and paracrine amplification of cytokine signals throughout the body 4
- TLR-driven responses that simultaneously trigger both inflammatory cascades 5
- Compartmentalized immune responses where systemic immunosuppression coexists with local tissue inflammation 3
Functional Consequences
Immune Cell Reprogramming
CARS manifests as selective silencing of acute pro-inflammatory genes while maintaining expression of certain anti-infectious genes 3. This is not global immune failure but targeted modification:
- Circulating leukocytes show altered surface molecule expression and cytokine production patterns 4
- Tissue leukocytes remain primed or activated despite systemic immunosuppression 3
- The immune system attempts to balance pathogen clearance with prevention of excessive tissue damage 3
Clinical Manifestations
When anti-inflammatory cytokines become systemically dominant, patients develop:
- Anergy (loss of delayed-type hypersensitivity responses) 4
- Markedly increased susceptibility to nosocomial infections 2, 3
- Enhanced vulnerability to secondary infectious complications 2
Critical Pitfalls in Understanding CARS
The original sequential model (SIRS followed by CARS) is oversimplified and often incorrect 5, 3. In reality:
- Both responses typically occur simultaneously from the onset of severe inflammation 5
- The relative magnitude and timing of each response—not their sequence—determines patient outcomes 1
- Animal "two-hit" models showing enhanced infection susceptibility are highly dependent on experimental procedures and may not fully reflect human pathophysiology 3
CARS should not be conceptualized as simple immunosuppression but as an adapted, compartmentalized response where systemic anti-inflammatory dominance coexists with maintained local immune function 3.
Triggering Conditions
CARS develops following: