Mechanisms of Indirect Acute Lung Injury

Abstract

Objective: To determine the contribution of programmed death receptor (PD)-1 in the morbidity and mortality associated with the development of indirect-acute lung injury. Background: The immune cell interaction(s) leading to indirect-acute lung injury are not completely understood. In this respect, we have recently shown that the murine cell surface coinhibitory receptor, PD-1, has a role in septic morbidity/mortality that is mediated in part through the effects on the innate immune arm. However, it is not know if PD-1 has a role in the development of indirect-acute lung injury and how this may be mediated at a cellular level. Methods: PD-1 -/- mice were used in a murine model of indirect-acute lung injury (hemorrhagic shock followed 24 hours after with cecal ligation and puncture-septic challenge) and compared to wild type controls. Groups were initially compared for survival and subsequently for markers of pulmonary inflammation, influx of lymphocytes and neutrophils, and expression of PD-1 and its ligand—PD-L1. In addition, peripheral blood leukocytes of patients with indirect-acute lung injury were examined to assess changes in cellular PD-1 expression relative to mortality. Results: PD-1 -/- mice showed improved survival compared to wild type controls. In the mouse lung, CD4⁺, CD11c⁺, and Gr-1⁺ cells showed increased PD-1 expression in response to indirect-acute lung injury. However, although the rise in bronchial alveolar lavage fluid protein concentrations, lung IL-6, and lung MCP-1 were similar between PD-1 -/- and wild type animals subjected to indirect acute lung injury, the PD-1 -/- animals that were subjected to shock/septic challenge had reduced CD4:CD8 ratios, TNF-α levels, MPO activity, and Caspase 3 levels in the lung. Comparatively, we observed that humans, who survived their acute lung injury, had significantly lower expression of PD-1 on T cells. Conclusions: PD-1 expression contributes to mortality after the induction of indirect-acute lung injury and this seems to be associated with modifications in the cellular and cytokine profiles in the lung.