An established body of literature supports the hypothesis that activation of a local tissue angiotensin (ANG) system in the extravascular tissue compartment of the lungs is required for lung fibrogenesis. Transcriptional activation of the angiotensinogen (AGT) gene is believed to be a critical and necessary step in this activation. This paper summarizes the data in support of this theory and discusses transcriptional regulation of AGT, with an emphasis on lung AGT synthesis as a determinant of fibrosis severity. Genetic data linking AGT polymorphisms to the severity of disease in Idiopathic Pulmonary Fibrosis are also discussed. 1. Introduction Pulmonary fibrosis results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and the obliteration of alveolar air spaces. If the etiology is unknown, the condition is designated as idiopathic pulmonary fibrosis (IPF) [1]. There are also several groups of xenobiotics or environmental toxins known to cause pulmonary fibrosis, for example, the antineoplastic agent bleomycin, the class III antiarrhythmic agent amiodarone, gamma-irradiation, silicon dust, and asbestos [2]. The main histological features of the fibrotic lung are persistent and unrepaired epithelial damage, proliferation and accumulation of fibroblasts and myofibroblasts, and increased collagen deposition [3]. This section will discuss evidence that lung-derived angiotensinogen (AGT) plays an important role in lung fibrogenesis. 2. Lung-Derived AGT in Lung Fibrogenesis Numerous studies support the existence of “local” angiotensin (ANG) systems in various organs and tissues. For example, the ANG II concentrations in the interstitial compartment of heart and eye were found to be 5–100 fold higher (about 50–500？pM) than that in plasma (~5–10？pM) [4, 5]. The higher interstitial levels of ANG II compared to the circulating level could not be explained by diffusion and/or receptor-mediated uptake of circulating angiotensin II. These results thereby suggest that tissue angiotensin II is largely, if not completely, synthesized locally. Furthermore, cultured cells from various organs including heart [6], vascular endothelium [7], brain [8–10], and lung [11] were shown to express the ANG system components such as AGT, ANG II, and their corresponding converting enzymes and angiotensin receptors. In contrast to the classical endocrine “renin-angiotensin-aldosterone system” (RAAS) in which the octapeptide angiotensin II is enzymatically cleaved from AGT by the actions of renin and angiotensin-converting enzyme
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