Fig. 1.

Transforming growth factor-beta (TGF-β) is activated and released from latency-associated protein (LAP) cover due to inflammatory response [31]. TGF-β binds to transforming growth factor-beta receptor (TGFβR1 and TGFβR2). TGFβR1 by SMAD2/3 causes the activation of phospholipase D (PLD1) [9, 34]. PLD1 decomposes phosphatidylcholine (PC) to phosphatidic acid (PA), and choline [9, 35]. PA activates phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1α) [9]. PIP5K1α converts phosphatidylinositol 4-phosphate (PIP4P) to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5) P2) [8, 9]. PtdIns(4,5) P2, by activation of NADPH oxidase4 (NOX4), increases ROS production. ROS causes internalization of the epithelial sodium channel (EnaC) [9, 28]. In addition, PtdIns(4,5) P2 has a positive feedback by activation of PLD1 [9, 36]. Also, TGFβR2 by co-operation with PI3K, increases the expression of NOX4 [37]. PLD1 too, by the effect on the gene, decreases the expression of the alpha subunit of EnaC. Non-functional EnaC causes pulmonary oedema [9]