Although acute lung injury (ALI) contributes significantly to critical illness, resolution often occurs spontaneously through endogenous pathways. We recently found that mechanical ventilation increases levels of pulmonary adenosine, a signaling molecule known to attenuate lung inflammation. Here, we hypothesized a contribution of transcriptionally controlled pathways to pulmonary adenosine receptor signaling during ALI. We gained initial insight from microarray analysis of pulmonary epithelia exposed to conditions of cyclic mechanical stretch - a mimic for ventilation-induced lung disease. Surprisingly, these studies revealed a selective induction of the ADORA2B. Utilizing real-time RT-PCR and western blotting, we confirmed an up to 9-fold induction of the ADORA2B following cyclic mechanical stretch (A549, Calu-3 or HPAEpiC). Studies utilizing ADORA2B promoter constructs identified a prominent region within the ADORA2B promoter conveying stretch responsiveness. This region of the promoter contained a binding site for the transcription factor hypoxia-inducible factor (HIF)-1. Additional studies utilizing site-directed mutagenesis or transcription factor binding assays demonstrated a functional role for HIF1 in stretch-induced increases of ADORA2B expression. Moreover, studies of ventilator induced lung injury revealed induction of the ADORA2B during ALI in vivo that was abolished following HIF-inhibition or genetic deletion of Hif1a. Together, these studies implicate HIF in the transcriptional control of pulmonary adenosine signaling during ALI.

This paper reviews the molecular basis of circadian rhythms and the pathophysiologic consequences of alterations in these rhythms, and explores the concept of daylight as therapy to restore disrupted circadian rhythms and improve clinical outcomes.

The adenosine A2b-receptor (Adora2b) has been implicated in cardio-protection from myocardial ischemia. As such the Adora2b was found to be critical in ischemic preconditioning (IP) or ischemia reperfusion (IR) injury of the heart. While the Adora2b is present on various cells types, the tissue specific role of the Adora2b in cardio-protection is still unknown. To study the tissue specific role of Adora2b signaling on inflammatory cells, endothelia or myocytes during myocardial ischemia in vivo, we intercrossed floxed Adora2b mice with Lyz2-Cre+, VE-Cadherin-Cre+ or Myosin-Cre+ transgenic mice, respectively. Mice were exposed to 60 minutes of myocardial ischemia with or without IP (4×5min) followed by 120 minutes of reperfusion. Cardio-protection by IP was abolished in Adora2bf/f-VE-Cadherin-Cre+ or Adora2bf/f-Myosin-Cre+, indicating that Adora2bs signaling on endothelia or myocytes mediates IP. In contrast, primarily Adora2b signaling on inflammatory cells was necessary to provide cardio-protection in IR injury, indicated by significantly larger infarcts and higher troponin levels in Adora2bf/f-Lyz2-Cre+ mice only. Cytokine profiling of IR injury in Adora2bf/f-Lyz2-Cre+ mice pointed towards PMNs. Analysis of PMNs from Adora2bf/f-Lyz2-Cre+ confirmed PMNs as one source of identified tissue cytokines. Finally, adoptive transfer of Ador2b−/− PMNs revealed a critical role of the Adorab2 on PMNs in cardio-protection from IR-injury. Adora2b signaling mediates different types of cardio-protection in a tissue specific manner. These findings have implications for the use of Adora2b agonists in the treatment or prevention of myocardial injury by ischemia.

The rotation of the earth and associated alternating cycles of light and dark–the basis of our circadian rhythms–are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the last few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly impact patient outcomes. Intriguingly, sedatives, anesthetics, and the ICU environment have all been shown to disrupt the circadian system in patients. In the current review we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts.

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