Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS).
Acute 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.



Blood 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.



ARDS 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).



Levels 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).



This 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.
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA. smonaghan@lifespan.org.
Sean F
0000-0003-1490-3043
SF
Monaghan
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Chun-Shiang
CS
Chung
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Yaping
Y
Chen
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Joanne
J
Lomas-Neira
MCB Department, Brown University, 70 Ship Street, Providence, RI, 02903, USA.
William G
WG
Fairbrother
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Daithi S
DS
Heffernan
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
William G
WG
Cioffi
Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown University and Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.
Alfred
A
Ayala
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D003710:Demography; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D013601:T-Lymphocytes / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D017252:CD3 Complex; D061026:Programmed Cell Death 1 Receptor
ARDS; Acute respiratory distress syndrome; Biomarker; Immunotherapy; PD-1; Soluble PD-1