title: Mechanisms of indirect acute lung injury: a novel role for the coinhibitory receptor, programmed death-1.
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.
authors: Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, Providence, RI, USA.
authors: Sean F
authors: SF
authors: Monaghan
authors: Rajan K
authors: RK
authors: Thakkar
authors: Daithi S
authors: DS
authors: Heffernan
authors: Xin
authors: X
authors: Huang
authors: Chun-Shiang
authors: CS
authors: Chung
authors: Joanne
authors: J
authors: Lomas-Neira
authors: William G
authors: WG
authors: Cioffi
authors: Alfred
authors: A
authors: Ayala
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D000328:Adult; D000368:Aged; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016516:CD4-CD8 Ratio; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009195:Peroxidase / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D015850:Interleukin-6; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D053148:Caspase 3