Role of AC7 and alcohol in innate immune responses during bacterial infection

项目总结/文摘

Project Summary/Abstract Alcohol consumption compromises the function of various components of the immune defense system by modulating innate and adaptive immunity in both humans and animal models. However, the mechanisms responsible for ethanol’s effects on the immune system are not fully understood. It is well established that cyclic AMP (cAMP) regulates immune responses; however, whether a specific adenylyl cyclase (AC) isoform is primarily responsible for mediating on ethanol’s effects on immune responses has not yet been clearly determined. Our long-term goal is to elucidate a) which specific isoform(s) of AC modulate(s) ethanol’s effects on immune responses, and b) the mechanisms underlying this modulation. Using myeloid lineage specific type 7 AC isoform (AC7) knockout mice, our preliminary data indicate that the suppressive effect of acute ethanol ingestion on cytokine expression in the lung requires AC7 expression in myeloid cells. Thus, we hypothesize that AC7 plays a key role in regulating the effects of acute alcohol ingestion on the immune system. We postulate that acute ingestion of alcohol results in an increase in one or more Gs-coupled receptor agonist(s) either locally in the lung or systemically in circulation. This, in turn, stimulates AC7 activity in myeloid cells, such as alveolar macrophages, resulting in suppression of immune responses. In this proposal, we will utilize the myeloid lineage specific AC7 knockout mice. We will employ acute alcohol ingestion combined with live bacteria peritoneal injection to elucidate the mechanisms by which ethanol suppresses innate immune responses via AC7 activity. This is a well-established mouse model for acute lung injury induced by sepsis in humans. The Specific Aims of the proposal are Aim 1: To determine innate immune responses in the lung of the myeloid lineage specific AC7 knockout mice in response to bacterial infection and acute ethanol treatment and Aim 2: To quantify Gs-coupled receptor agonists in bronchoalveolar lavage fluid and plasma and cAMP levels in the lungs of animals treated with alcohol and live bacteria. We postulate that adenosine, adrenaline, and prostaglandin E2 are the prime candidates for Gs-coupled receptor agonists increasing by acute ethanol ingestion. The proposed study is concise and focused on acute alcohol effects on lung inflammation caused by bacterial infection. Results from the proposed studies will generate mechanistic information regarding the effects of alcohol on the immune system via AC7 activity. The data derived from this study will become a foundation for future research in which mechanistic aspects of alcohol effects on immune system are studied in detail and may lead to a pharmacological intervention to counter negative consequences of alcohol ingestion.