Pulmonary macrophage inhibition and inhaled nitric oxide attenuate lung ischemia-reperfusion injury.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is postulated to occur biphasically. Donor pulmonary macrophages mediate early injury, and neutrophil-dependent injury predominates in the later phase of LIRI. We hypothesized that the biphasic response to LIRI would be attenuated by the administration of gadolinium, a known pulmonary macrophage inhibitor, and inhaled nitric oxide (NO), a pulmonary vasodilator that also interferes with neutrophil chemotaxis. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, study groups (n = 10 per group) underwent two hours of reperfusion after 18 hours of cold ischemia (4 degrees C). Lungs received gadolinium alone, or inhaled NO in the presence or absence of macrophage inhibition with gadolinium. RESULTS: Compared with control animals, pulmonary macrophage inhibition with the concurrent administration of inhaled NO increased lung compliance (p < 0.01) and oxygenation (p = 0.03), while also decreasing pulmonary artery pressure (p < 0.01), myeloperoxidase content by 63% (p < 0.01), wet to dry ratios by 23% (p < 0.01), and lung tissue (p < 0.01) and bronchoalveolar lavage tumor necrosis factor-alpha (TNF-alpha) protein levels (p < 0.01). CONCLUSIONS: The severity of LIRI was most significantly reduced by the inhibition of pulmonary macrophages and the concomitant use of inhaled NO. Pulmonary macrophages, likely through the elaboration of proinflammatory cytokines such as TNF-alpha, not only cause early injury themselves but also prime cells such as neutrophils to injure lungs in the later stages of LIRI. The LIRI was effectively blunted by the reduction of macrophage-dependent injury by gadolinium while inhaled NO also attenuated injury by reducing pulmonary hypertension and minimizing neutrophil sequestration.

Requirement for tumor necrosis factor-receptor 2 in alveolar chemokine expression depends upon the form of the ligand.

Respiratory virus infection evokes a potent T-cell response that may result in a considerable insult to the structural and functional integrity of the gas exchange units of the lung. Alveolar antigen recognition by CD8+ T lymphocytes results in significant injury that is critically dependent upon tumor necrosis factor (TNF)-alpha expressed by the CD8+ T cells and is largely dependent upon TNF-receptor 1 expression on the alveolar epithelial target cells. TNF-receptor 2 (TNF-R2)-deficient mice were used to demonstrate that CD8+ T-cell-mediated lung injury associated with clearance of experimental influenza requires TNF-R2 for full expression of immunopathology. In vitro analysis indicates that alveolar cell expression of TNF-R2 is critical in the induction of epithelial monocyte chemoattractant protein (MCP)-1 expression specifically in response to soluble TNF-alpha, suggesting an important role for this receptor in bystander lung injury. However, TNF-R2 was dispensable for induction of alveolar MCP-1 expression in response to transmembrane TNF-alpha expressed by antigen-specific CD8+ T cells, and the effects of the two receptors seem to be additive. Because TNF-R2 may be rapidly shed as part of feedback inhibition of bystander inflammation, this suggests a mechanism by which immunopathology in respiratory virus infection may be regulated and by which T-cell receptor-dependent TNF-alpha activity might bypass such negative regulation for contact-dependent antiviral activities.

Cutting edge: pulmonary immunopathology mediated by antigen-specific expression of TNF-alpha by antiviral CD8+ T cells.

Respiratory virus infection results in considerable pulmonary immunopathology, a component of which results from the host immune responses. We have developed a murine model to specifically examine the lung injury due to CD8(+) T cell recognition of an influenza hemagglutinin (HA) transgene on lung epithelium in the absence of replicating virus, after adoptive transfer. Lung injury is largely mediated by chemokines expressed by the epithelial cells upon T cell recognition mediated by TNF-alpha. To determine the critical source of TNF-alpha, HA-specific TNF(-/-) CD8(+) T cells were transferred into HA transgenic animals, and lung injury was not observed, though these T cells exhibited no defect in antiviral activity in vivo. This indicates that the initiating event in the injury process is Ag-specific expression of TNF-alpha by antiviral CD8(+) T cells upon recognition of alveolar epithelial Ag, and that the effector activities responsible for viral clearance may be dissociable from those resulting in immunopathology.