Surfactant metabolism (Homo sapiens)
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The alveolar region of the lung creates an extensive epithelial surface that mediates the transfer of oxygen and carbon dioxide required for respiration after birth. Type I epithelial cells form the alveolar surface and mediate gaseous exchange. Type II epithelial cells secrete pulmonary surfactant, a lipoprotein complex that forms a thin interfacial film, lowering surface tension at the air-liquid interface in alveoli and maintaining the structural integrity of alveoli, preventing their collapse at low volumes (Agassandian & Mallampalli 2013). Surfactant production is increased prior to birth, in preparation for air breathing at birth (Hallman 2013). Pre-term infants, where type II epithelial cells are not fully differentiated yet, can produce insufficient surfactant and result in respiratory distress syndrome. Surfactant is composed primarily of phospholipids enriched in phosphatidylcholine (PC) and phosphatidylglycerol (PG) (Agassandian & Mallampalli 2013) and the pulmonary collectins, termed surfactant proteins A, B, C and D (SFTPA-D). They influence surfactant homeostasis, contributing to the physical structures of lipids in the alveoli and to the regulation of surfactant function and metabolism. They are directly secreted from alveolar type II cells into the airway to function as part of the surfactant. SFTPA and D are large, hydrophilic proteins while SFTPB and C are small, very hydrophobic proteins (Johansson et al. 1994). In addition to their surfactant functions, SFTPA and D play important roles in innate host defense by binding and clearing invading microbes from the lung (Kingma & Whitsett 2006). Nuclear regulation, transport, metabolism, reutilisation and degradation of surfactant are described here (Ikegami 2006, Boggaram 2009, Whitsett et al. 2010). Mutations in genes involved in these processes can result in respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases (Perez-Gil & Weaver 2010, Whitsett et al. 2010, Akella & Deshpande 2013, Jo 2014).
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Both ADORA receptors mediate their actions by coupling with the G protein alpha s subunit which activates adenylyl cyclase and increases intracellular cAMP concentrations. In surfactant physiology, the receptor:adenosine complex positively regulates surfactant export from lamellar bodies. (Cooper JA et al, 1995; Linden J et al, 1999). Adenosine deaminase (CECR1, ADA2) degrades extracellular adenosine (Ade-Rib), reducing or neutralising the positive regulatory effect of adenosine in surfactant export.
Defects in SLC34A1 are the cause of hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1) (Prie et al. 2002). Defects in SLC34A2 are a cause of pulmonary alveolar microlithiasis, a rare disease characterised by the deposition of calcium phosphate microliths throughout the lung (Corut et al. 2006).