TRANSFORMING GROWTH FACTOR ALPHA AND LUNG INJURY

本应用旨在确定转化生长因子α (TGFalpha)对肺损伤炎症反应的影响。TGFalpha是一种在肺部发育过程中发现的蛋白质，它由肺中的大多数细胞产生，并仅与表皮生长因子受体（EGF-R）结合。使用SP-C启动子在远端肺中表达人TGFalpha的转基因小鼠在暴露于加热的特氟龙超细颗粒（UFP）引起的急性肺损伤后，与野生型（wt）对照相比，表现出更高的存活率和更少的炎症。本实验验证了TGFalpha减轻急性肺损伤炎症反应的假说。为了直接确定TGFalpha在体内的作用，我们将在UFP暴露前和暴露期间通过腺病毒基因载体给wt小鼠注射TGFalpha，并评估其肺部炎症和损伤程度，与未治疗的对照组进行比较。为了确定TGFalpha抗炎特性的机制，我们将确定TGFalpha对炎症介质表达、抗氧化酶活性以及损伤后细胞增殖和凋亡部位的影响。为了确定TGFalpha对炎症作用所需的细胞区室，我们将比较仅在II型细胞中缺乏EGF-R信号的小鼠与在所有细胞中缺乏EGF-R信号的小鼠暴露于UFP后的炎症反应。这项应用将确定TGFalpha减少肺损伤和损伤后炎症的作用和机制，并可能在治疗和预防临床显著急性肺损伤方面具有未来价值。这项提案的首席研究员（PI）已经完成了儿科肺部医学的奖学金，并开始了他作为肺部医学和生物学部门助理教授的第一年，他在基础研究方面的投入超过75%。在整个培训过程中，他表现出了持续的兴趣和能力，完成基础科学研究，这在他的出版物中有所体现。RCA将允许PI在杰夫·惠特塞特（Jeff Whitsett）博士指导的儿童医院肺生物学部门继续发展。肺生物学部由一组高度互动的独立高级研究人员组成，他们在表面活性剂生物学、肺发育、肺损伤机制和囊性纤维化方面进行了资助研究。提出的实验将允许P.I.发展一个独立的研究部门，致力于了解各种肺部疾病的基本病理生物学。

The present application seeks to determine the effects of transforming growth factor alpha (TGFalpha) on the inflammatory response to lung injury. TGFalpha is a protein found throughout lung development where it is produced by most cells in the lung and binds exclusively to the epidermal growth factor receptor (EGF-R). Transgenic mice expressing human TGFalpha in distal lung using the SP-C promoter demonstrate increased survival and reduced inflammation compared with wild type (wt) controls following acute lung injury caused by exposure to heated Teflon ultrafine particles (UFP). The present application tests the hypothesis that TGFalpha reduces the inflammatory response in acute lung injury. To directly determine the role of TGFalpha in vivo, we will administer TGFalpha to wt mice intraperitoneally, intratracheally, and through adenoviral gene vectors before and during UFP exposure and assess the degree of lung inflammation and injury compared with untreated controls. To determine the mechanisms of TGFalpha's anti-inflammatory properties we will determine TGFalpha's effects on the expression of inflammatory mediators, antioxidant enzyme activity, and cellular sites of proliferation and apoptosis following injury. To determine the cellular compartments required for TGFalpha's effects on inflammation, we will compare the inflammatory response following UFP exposure in mice with deficiency of EGF-R signaling in type II cells only, to mice with deficiency of EGF-R signaling in all cells. This application will determine the role and delineate mechanisms by which TGFalpha reduces lung damage and inflammation following injury, and may be of future value in treating and preventing clinically significant acute lung injury. The principal investigator (PI) for this proposal has completed a fellowship in pediatric pulmonary medicine and is beginning his first year as an Assistant Professor in the Divisions of Pulmonary Medicine and Biology with greater than 75 percent effort in basic research. Throughout his training he has demonstrated a continued interest and ability to accomplish basic science investigation as indicated in his publications. The RCA will allow the PI to continue to develop in the Division of Pulmonary Biology at Children's Hospital directed by Dr. Jeff Whitsett. The Pulmonary Biology Division consists of a highly interactive group of independent senior investigators with funded research efforts in surfactant biology, lung development, mechanisms of lung injury, and cystic fibrosis. The experiments proposed will permit the P.I. to develop an independent line of research in a division dedicated to understanding the basic pathobiology of various lung diseases.