Abstract
BackgroundAcute respiratory distress syndrome (ARDS) remains a common organ dysfunction in the critically ill patient. Mechanisms for its development have focused on immune mediated causes, aspects of our understanding are not complete, and we lack biomarkers.Design, setting, and subjectsBlood and bronchial alveolar lavage fluid (BAL) from humans (n = 10–13) with ARDS and controls (n = 5–10) as well as a murine model of ARDS (n = 5–6) with controls (n = 6–7) were studied.MethodsARDS was induced in mice by hemorrhagic shock (day 1) followed by poly-microbial sepsis (day 2). Samples were then collected on the third day after the animals were euthanized. Ex vivo experiments used splenocytes from animals with ARDS cultured with and without soluble programmed death receptor-1 (sPD-1).ResultsLevels of sPD-1 are increased in both the serum (11,429.3 pg/mL(SD 2133.3) vs. 8061.4(SD 4187.8), p = 0.036) and bronchial alveolar lavage (BAL) fluid (6,311.1 pg/mL(SD 3758.0) vs. 90.7 pg/mL(SD 202.8), p = 0.002) of humans with ARDS. Similar results are seen in the serum (9396.1 pg/mL(SD 1546.0) vs. 3464.5 pg/mL(SD 2511.8), p = 0.001) and BAL fluid (2891.7 pg/mL(SD 868.1) vs. 1385.9 pg/mL(SD 927.8), p = 0.012) of mice. sPD-1 levels in murine blood (AUC = 1(1–1), p = 0.006), murine BAL fluid (AUC = 0.905(0.717–1.093), p = 0.015), and human BAL (AUC = 1(1–1), p = 0.001) fluid predicted ARDS. To assess the importance of sPD-1 in ARDS, ex vivo experiments were undertaken. BAL fluid from mice with ARDS dampens the TNF-α production compared to cells cultured with BAL lacking sPD-1 (2.7 pg/mL(SD 3.8) vs. 52.38 pg/mL(SD 25.1), p = 0.002).ConclusionsThis suggests sPD-1 is elevated in critical illness and may represent a potential biomarker for ARDS. In addition, sPD-1 has an anti-inflammatory mechanism in conditions of marked stress and aids in the resolution of severe inflammation. sPD-1 could be used to not only diagnose ARDS, but may be a potential therapy.
Highlights
Acute respiratory distress syndrome (ARDS) remains a common organ dysfunction in the critically ill patient
PD‐1 and sPD‐1 expression in ARDS The expression of Programmed death receptor-1 (PD-1) on lymphocytes was compared in critically ill patients with ARDS (n = 21) to other ICU patients without ARDS (n = 9)
The levels of PD-1 expression on CD3+ T-cells were significantly increased in patients with ARDS (Fig. 1c)
Summary
Acute respiratory distress syndrome (ARDS) remains a common organ dysfunction in the critically ill patient. Acute conditions like sepsis and ARDS have been influenced by the expression of PD-1. In both humans and mice, PD-1 appears to play a role in the pathology as well as outcomes from sepsis [6,7,8] and ARDS [9]. In sepsis the influence of PD-1 appears to be modulated through expression on macrophages as survival is improved in animals lacking PD-1 [8]. The survival benefit of mice lacking PD-1 with ARDS appears to be due to alterations in cell ratio, TNF expression and neutrophil function [9]
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