Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis

V. Eric Kerchberger, Julie A. Bastarache, Ciara M. Shaver, Hiromasa Nagata, J. Brennan McNeil, Stuart R. Landstreet, Nathan D. Putz, Wen Kuang Yu, Jordan Jesse, Nancy E. Wickersham, Tatiana N. Sidorova, David R. Janz, Chirag R. Parikh, Edward D. Siew, Lorraine B. Ware

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Acute respiratory distress syndrome (ARDS) is an inflammatory lung disorder that frequently complicates critical illness and commonly occurs in sepsis. Although numerous clinical and environmental risk factors exist, not all patients with risk factors develop ARDS, raising the possibility of genetic underpinnings for ARDS susceptibility. We have previously reported that circulating cell-free hemoglobin (CFH) is elevated during sepsis, and higher levels predict worse outcomes. Excess CFH is rapidly scavenged by haptoglobin (Hp). A common HP genetic variant, HP2, is unique to humans and is common in many populations worldwide. HP2 haptoglobin has reduced ability to inhibit CFH-mediated inflammation and oxidative stress compared with the alternative HP1. We hypothesized that HP2 increases ARDS susceptibility during sepsis when plasma CFH levels are elevated. In a murine model of sepsis with elevated CFH, transgenic mice homozygous for Hp2 had increased lung inflammation, pulmonary vascular permeability, lung apoptosis, and mortality compared with wild-Type mice. We then tested the clinical relevance of our findings in 496 septic critically ill adults, finding that HP2 increased ARDS susceptibility after controlling for clinical risk factors and plasma CFH. These observations identify HP2 as a potentially novel genetic ARDS risk factor during sepsis and may have important implications in the study and treatment of ARDS.

元の言語English
記事番号e131206
ジャーナルJCI Insight
4
発行部数21
DOI
出版物ステータスPublished - 2019 11 1

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ASJC Scopus subject areas

  • Medicine(all)

これを引用

Eric Kerchberger, V., Bastarache, J. A., Shaver, C. M., Nagata, H., Brennan McNeil, J., Landstreet, S. R., Putz, N. D., Kuang Yu, W., Jesse, J., Wickersham, N. E., Sidorova, T. N., Janz, D. R., Parikh, C. R., Siew, E. D., & Ware, L. B. (2019). Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis. JCI Insight, 4(21), [e131206]. https://doi.org/10.1172/jci.insight.131206