期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 10, 页码 E2302-E2310出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716747115
关键词
heme oxygenase; circadian rhythm; DAMPS; innate immunity; adenosine
资金
- NIH Award [R44 DK111260-01]
- Department of Defense Award [W81XWH-16-0464]
- Sao Paulo Research Foundation (FAPESP) Grant [2011/19581-8]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [11/19581-8] Funding Source: FAPESP
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.
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