## 3 Expression of Estrogen Receptors by Mammalian Lungs and Their Physiological Roles  
Broadly, ERs are divided into two types--ER-alpha (ER\(\alpha\)) and ER-beta (ER\(\beta\))--each having various splice variants and tissue-specific expression. These ER variants are generated either by alternative splicing, initiation of translation [109; 110] or proteolysis [111]. It was [PERSON] and groupmates who for the first time characterized the tissue-specific distribution of ER\(\alpha\) and ER\(\beta\) transcripts in rats and claimed ER\(\beta\) as the predominant isoform prevailing in the lungs [112]. Later on, other studies also detected both ERs in the lung tissues and cell lines [49; 113]. In healthy lung tissues, pneumocytes and bronchial epithelial cells are the predominant sites of ER expression, and sex steroids have effects both on the normal physiology and diseased conditions [8; 9]. The study by [PERSON] and colleagues ascertained the ER subcellular localization including that of cytoplasm, nucleus, etc., in normal bronchial epithelial cells as well as NSCLC cells. Their results confirm the prior observations of [PERSON] and associates that bronchial epithelial cells express nearly twice as much ER\(\beta\) than ER\(\alpha\)[50; 114]. ER knockout mice models were used to understand the importance of ER\(\alpha\), ER\(\beta\) or both in the overall phenotype as well as the development and function of lungs. Interestingly, ER\(\alpha\) null mice showed no phenotypic alteration in the lungs [47]. However, working on ER\(\beta\) knockout mice, [PERSON] and accomplices observed ER\(\beta\) as the regulator of lung alveoli population, surfactant protein production and overall homeostasis of the lung tissues [115]. The results of this study indicate that the lungs of ER\(\beta\) knockout female mice exhibited reduced surfactant protein, platelet-derived growth factor A (PDGF-A) and granulocyte macrophage colony-stimulating factor (GM-CSF) expressions. Another study by [PERSON] and colleagues revealed that at 5 months of development, both male and female ER\(\beta\)-deficient adult mice exhibited abnormal extracellular matrix deposition and alveolar collapse, together resulting in systemic hypoxia [116]. This observation further suggests that ER\(\beta\) is involved in the structural and functional development of lungs in both adult male and female mice, in a ligand-independent manner, or that estrogens act via a local autocrine mechanism. In another attempt, [PERSON] and colleagues used 26 different tissues, including those of lungs from transgenic and ovariectomized female mice models for ERE-luciferase reporter assay activities against 17\(\beta\)-estradiol-ERs stimulation. Significantly, their results show that lungs in these mice models displayed 17\(\beta\)-estradiol-ER-dependent \(\sim\)15-fold induction of luciferase reporter gene activity. This study identified lungs as the most important target tissues of the mice model for the estrogen-mediated cellular actions [117]. In a similar ERE-luciferase reporter gene assay in both male and female mouse models, [PERSON] and teammates also identified lungs as an important target site for 17\(\beta\)-estradiol activities [118]. Of note, under completely normal physiological conditions, 17\(\beta\)-estradiol/E2 is the major estrogen present in females. The likelihood of ER\(\beta\) playing more important and decisive control activities in lungscontrary to the ER\(\alpha\) is further strengthened by the microarray data, revealing ER\(\beta\) tumor expression as linked with nearly 500 gene variations contrary to a mere 20 for ER\(\alpha\)[119]. All these studies collectively indicate that estrogens and ERs, particularly ER\(\beta\), not only play multiple important roles toward maintaining a healthy lung physiology but are also associated more strongly with LC intracellular transformations.