Mechanistic insights into cell-free hemoglobin-induced injury during septic shock
Jeffrey Wang, Willard N. Applefeld, Junfeng Sun, Steve B. Solomon, Jing Feng, Zoe G. Couse, Thomas Risoleo, Robert L. Danner, Jesús Tejero, Juan J.L. Lertora, Elmira Alipour, Swati Basu, Vandana Sachdev, Daniel B. Kim‐Shapiro, Mark T. Gladwin, Harvey G. Klein, Charles Natanson
Abstract
Cell-free hemoglobin (CFH) elevations are a known consequence of clinical sepsis. Using a two-by-two factorial design and extensive physiological and biochemical evidence, we found a direct mechanism of injury related to nitric oxide scavenging leading to pulmonary hypertension increasing right heart afterload, depressed cardiac function, worsening circulatory failure, and death, as well as an indirect mechanism related to iron toxicity. These discoveries alter conventional thinking about septic shock pathogenesis and provide novel therapeutic approaches.