Growth Factor Protection in Acute Lung Injury

急性肺损伤预后差，病因多样。已经确定了许多诱发因素，但关于控制这种复杂情况的病理生理机制及其与治疗策略的关系仍然存在疑问。急性肺损伤以上皮损伤和表面活性剂功能丧失为特征，可导致生长因子激活，包括转化生长因子- α (TGFalpha)和tgf - β的激活。反过来，这些生长因子控制增殖和参与分化功能的基因的转录。先前，一个含有TGFalpha的基因位点与急性肺损伤有关，TGFalpha转基因小鼠从急性肺损伤中获救。其他数据表明，这些作用可能是通过位于呼吸道上皮细胞上的EGFR介导的。已产生条件TGFalpha转基因小鼠，以便详细研究该生长因子在肺损伤中的时间作用。最近，我们发现TGFbeta被释放，并且在我们的急性肺损伤模型中许多TGFbeta应答转录物被改变。我们的中心假设是TGFalpha和TGFbeta信号通路之间的相互作用通过改变对肺功能至关重要的转录程序来决定急性肺损伤的生存和后遗症。为了进一步评估TGFalpha和TGFbeta在急性肺损伤中的作用，我们建议操纵TGFalpha信号传导并监测TGFbeta信号传导的影响。本建议的具体目标力求：1)确定急性肺损伤中TGFalpha/EGFR介导保护的分子机制；2)评估急性肺损伤中TGFalpha诱导和TGFalpha/EGFR信号传导的治疗效果，并确定肺纤维化是否是作为保护的必要后遗症；3)确定TGFalpha和TGFbeta相互作用调节关键基因表达的遗传机制。重点研究控制sfpb启动子活化的顺式作用元件。这项研究具有创新性，因为它将直接评估TGFalpha/EGFR信号的潜在治疗益处，以及TGFalpha与TGFbeta在急性肺损伤中的可能相互作用。在本项目完成后，我们期望：1)确定TGFalpha调节的导致急性肺损伤保护的转录事件；2)更好地了解TGFbeta在急性肺损伤中的功能；3)确定肺纤维化是否是急性肺损伤期间激活TGFalpha/EGFR信号的不良后果。这些研究的预期影响将是基于证据的科学验证或反驳针对TGFalpha/EGFR信号传导的治疗方法可被考虑用于治疗急性肺损伤的可能性。

Acute lung injury has a poor prognosis and a diverse etiology. Numerous precipitating factors have been identified, yet questions remain about the pathophysiological mechanisms controlling this complex condition and their relationship to therapeutic strategies. Marked by epithelial damage and loss of surfactant function, acute lung injury can lead to growth factor activation, including activation of transforming growth factor-alpha (TGFalpha) and TGFbeta. These growth factors, in turn, control proliferation and the transcription of genes involved in differentiated function. Previously, a genetic locus that harbors TGFalpha was linked to, and TGFalpha transgenic mice were rescued from, acute lung injury. Additional data imply that these effects may be mediated through EGFR located on respiratory epithelial cells. Conditional TGFalpha transgenic mice have been generate to permit detailed investigations of the temporal role of this growth factor in lung injury. Recently, we found TGFbeta is released, and many TGFbeta responsive transcripts are altered in our model of acute lung injury. Our central hypothesis is that the interplay between TGFalpha and TGFbeta signaling pathways determines survival and the sequelae resulting from acute lung injury by altering transcriptional programs critical to lung function. To further assess the role of TGFalpha and TGFbeta in acute lung injury, we propose to manipulate TGFalpha signaling and monitor the consequences on TGFbeta signaling. The Specific Aims of this proposal seek to: 1) Identify the molecular mechanisms responsible for TGFalpha/EGFR mediated protection in acute lung injury, 2) Evaluate the therapeutic efficacy of TGFalpha induction and TGFalpha/EGFR signaling during acute lung injury and determine whether pulmonary fibrosis is a necessary sequela as a consequence of protection, and 3) Determine the genetic mechanisms of TGFalpha and TGFbeta interactions that modulate critical gene expression, focusing on the cis-acting elements that control Sftpb promoter transactivation. This research is innovative because it will directly evaluate the potential therapeutic benefits of TGFalpha/EGFR signaling and the possible interactions of TGFalpha with TGFbeta in acute lung injury. At the completion of this project, we expect to: 1) Identify the transcriptional events modulated by TGFalpha that leads to protection from acute lung injury, 2) Gain a better understanding of how TGFbeta functions in acute lung injury, and 3) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFalpha/EGFR signaling during acute lung injury. The anticipated impact of these studies would be an evidence-based scientific verification or refutation of the likelihood that therapeutics directed at TGFalpha/EGFR signaling could be considered for the treatment of acute lung injury.