Nitric oxide regulation of lung surfactant protein B (SP-B) gene expression.

摘要

Pulmonary surfactant maintains alveolar integrity during respiration by reducing surface tension at the alveolar air-tissue interface. Surfactant protein B (SP-B), an 8 kD hydrophobic protein of pulmonary surfactant, is essential for surfactant function. SP-B deficiency impairs surfactant function causing alveolar instability and respiratory failure. SP-B is expressed in a cell/tissue-specific manner by the alveolar type II and Clara cells of the lung and is developmentally induced. In a number of inflammatory diseases of the lung, such as acute respiratory distress syndrome (ARDS), acute pneumonia, acute respiratory syncitial virus (RSV) infection in infants, and others lung injury is associated with elevated levels of ·NO. We hypothesized that elevated ·NO levels as found in inflammatory diseases adversely affect surfactant system contributing to lung injury. In the present study, we studied the effects of ·NO on SP-B gene expression in NCI-H441 cells, a human lung cell line with characteristics of Clara cells, and in MLE-12 cells, a mouse lung cell line with characteristics of type II cells. Our studies showed that ·NO donors inhibited SP-B mRNA levels in a dose- and time-dependent manner indicating that elevated levels of ·NO negatively affect SP-B gene expression. Our studies also showed that ·NO donors inhibited SP-B gene expression by inhibiting gene transcription. The minimal SP-B promoter (−233/+41 bp) was sensitive to ·NO inhibition in H441 cells indicating the presence of ·NO response elements with the minimal promoter. Our studies also showed the ·NO acted independently of cGMP signaling pathway to inhibit SP-B gene expression. Our studies suggest that elevated ·NO levels as found in inflammatory diseases of the lung can adversely affect SP-B levels contributing to lung injury.