Innate Immune Responses in Ventilator-Associated Pneumonia

Ventilator-associated pneumonia (VAP) is a common complication of mechanical ventilation, resulting in substantial morbidity, mortality, and health care cost. Early upper airway colonization by pathogenic bacteria and microaspiration are the primary pathogenic events leading to VAP. Patients at risk for VAP have defects in structural/mechanical defenses of the respiratory tract. In addition, critical illness, including sepsis, trauma, and postoperative states, is associated with profound defects in both innate and acquired antibacterial immunity, influencing antimicrobial effector functions of both leukocytes and structural/parenchymal cells. Factors present within the lung microenvironment, including alveolar stretch, cyclical atelectasis, changes in oxygen tension, and respiratory tract microbiota, substantially impact antibacterial host responses. Mechanisms accounting for dysregulated immune homeostasis are incompletely understood, but likely involve: (1) alterations in the balance of pro- and anti-inflammatory cytokines; (2) changes in pathogen recognition receptor and G-protein coupled receptor expression and downstream signaling cascades; and (3) dysregulated cell death responses. Antibiotics and preventive strategies are the mainstay of therapy in patients with VAP. However, novel approaches are needed to reverse immunological reprogramming that occurs during critical illness and/or mechanical ventilation, and to identify patients who are most likely to benefit from immunomodulatory therapy.