Hauser, Carl J.
Saraiva Camara, Niels Olsen
Robson, Simon C.
Otterbein, Leo E.
Total Authors: 11
 Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Surg, Transplant Inst, Boston, MA 02215 - USA
 Hillhurst Biopharmaeut Inc, Montrose, CA 91020 - USA
 Harvard Med Sch, Transplant Inst, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 - USA
 Georgia State Univ, Dept Chem, Atlanta, GA 30303 - USA
 Emory Univ, Ctr Diagnost & Therapeut, Atlanta, GA 30303 - USA
 Univ Sao Paulo, Lab Transplantat Immunobiol, Dept Immunol, Inst Biomed Sci, BR-05508900 Sao Paulo - Brazil
Total Affiliations: 6
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA;
MAR 6 2018.
Web of Science Citations:
Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39(-/-) and Per2(-/-) mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction. (AU)