Acute Inflammatory Lung Injury: Mechanisms and Interventions

Abstract

Acute inflammatory responses involving the lung occur rather commonly during adult respiratory distress syndrome (ARDS), during intrapulmonary presence of infectious agents (bacteria, viruses), after ischemia reperfiision events, and in a variety of other situations. The key issues to be addressed are: identifying the triggers for these inflammatory responses, defining the role of complement and the participation of leukocytes, and determining the requirements for cytokines and the role of adhesion molecules in these events. Experimental rat models have provided important insights into mechanisms of acute lung injury. The first model is produced by systemic activation of complement following intravenous infusion of purified cobra venom factor (CVF). Infusion of CVF results in intravascular activation of neutrophils and upregulation of neutrophil CDllb/CD18, resulting in intrapulmonary sequestration and oxidant-mediated damage of vascular endothelial and alveolar epithelial cells. In this model the morphological features in rat lungs are similar to those found in human ARDS. Injury in this lung model is neutrophil- and complement-dependent, cytokine-independent, and requires β₂ integrins (LFA-1, Mac-1), ICAM-1 and L- and P-selectins. Blocking of any of the relevant adhesion molecules reduces neutrophil accumulation and tissue injury. In the second model, injury follows intrapulmonary deposition of IgG immune complexes and extensive intra-alveolar accumulation of neutrophils. The morphological features of this inflammatory reaction would be akin to inflammatory responses to infectious bacterial agents in lung. In this model complement and neutrophils are both required for induction of injury. Neutrophil recruitment requires β₂ integrins (CD1la/CD 18), ICAM-1, E- and L-selectins, and cytokines (IL-1, TNFα). Injury is due to combined release of oxidants and proteases from lung macrophages and recruited neutrophils. The third model of acute lung injury follows in vivo ischemia, (followed by reperfiision) of distal extremities. Pulmonary vascular damage occurs, is complement- and neutrophil-dependent, and requires participation of cytokines (TNFα and IL-1) and adhesion molecules (CD11 a/CD 18, CD11b/CD18, L- and E-selectin). Thus, inflammatory lung injury varies with respect to the causes of injury, the cytokines involved, and the requirement for adhesion molecules. In all cases lung injury can be reduced by appropriate blocking of adhesion molecules and cytokines.

Inflammatory responses are assumed to play major roles in events that lead to acute tissue injury and, ultimately, multiorgan failure. The triggers that drive these adverse responses may be extrinsic (such as bacteria, bacterial lipopolysaccharide, viruses, etc.) or may be the result of activation of proinflammatory cascades (e.g., an immune response, complement activation, cytokine expression, etc.). Identifying the factors responsible for initiation of inflammatory cascades and understanding the mechanisms responsible for ensuing tissue damage are critical to development of more effective therapeutic interventions. The following studies involving the use of animal models of lung injury provide insights into mechanisms of inflammatory tissue damage and how the injury can be effectively averted.