Structure, function and deficiency diseases of lung surfactant protein-c

Abstract

Pulmonary surfactant is a mixture of lipids and hydrophobic surfactant proteins B (SP-B) and SP-C and hydrophilic proteins SP-A and SP-D. Pulmonary surfactant reduces the surface tension at the air-water interface of the lung alveoli by forming a surface active film. In this way, it prevents alveoli from collapsing and facilitates the process of breathing. SP-C cooperates with SP-B to enhance the surface active properties of surfactant phospholipids. Reports on the association of lung disease with SP-C deficiency have led to new insights into the importance of SP-C for proper surfactant homeostasis. In most animal species the major form of SP-C is a 35-residue peptide chain which contains two thioester-linked palmitoyl groups, giving a total molecular mass of 4.2 kDa. Though t he function of SP-C in vivo remains unclear, but effects of SP-C on the adsorption, spreading, and stability of lipid films at an air ⁄ water interface have been documented in a number of in vitro studies. Genetic disorders disrupting normal surfactant metabolism (surfactant dysfunction disorders) have been recognized in the neonatal and pediatric populations. Although rare, these disorders cause significant mortality and morbidity, including acute respiratory distress and failure in full-term neonates, and interstitial lung disease (ILD) in older infants, children, and adults. The genes involved in these disorders are critical for surfactant production and function in the lung and include SP-C gene ( SFTPC ) besides others . More than 40 mutations in the SFTPC gene have been identified in people with dysfunction of lung surfactant. Mutations in the SFTPC gene result in the reduction or absence of mature SP-C and accumulation of abnormal forms of SP-C, resulting into breathing problems in newborns and onset of breathing difficulties in children and adults. SFTPC gene mutations associated with surfactant dysfunction affect the processing of the SP-C protein. Many of these mutations occur in a region of gene called the BRICHOS domain, which appears to be involved in the processing of SP-C protein. It is not known which of these outcomes causes the symptoms of SP-C dysfunction. Recent reports suggest that abnormally processed SP-C proteins form altered three-dimensional shape and accumulate inside lung cells. These misfolded proteins may trigger a cellular response that results in cell damage and death. Mutations in BRICHOS domain of SP-C have been associated to ER stress, proteasome dysfunction, and apoptosis. This article reviews information on structure and function of SP-C and the associated mutations in SFTPC gene in relation to SP-C deficiency diseases.