The role of serine protease in diaphragm development

Abstract

Congenital diaphragmatic hernias (CHD) are common birth defects that often have severe medical consequences. CHD occurs from the failure of diaphragm development, which leads to a herniation or elevation of abdominal components into the pleural cavity, and results in respiratory failure. Here we report that type II transmembrane serine protease‐1 (TMPRSS1)‐null mice exhibit defective diaphragms that mimic the phenotypes of the diaphragm elevation in humans. Histology and morphometry analyses showed that the tendinous muscle, but not the muscular layer in the diaphragm of the TMPRSS1‐null mice was significantly thinner than in the wild‐type mice. This phenomenon resulted in the position of the diaphragm and liver shifting upward, and the restricted expansion of the lung. We also observed that the pulmonary functions, such as lung resistance and compliance were also significantly impaired in the TMPRSS1‐null mice. To investigate the role of TMPRSS1 during the embryonic development of the diaphragm, we compared the area of diaphragm precursor structure, pleuroperitoneal folds (PPF) and the number of muscle progenitor cells and fibroblasts in the PPF between TMPRSS1‐null and wild‐type embryos (E13.5). The results showed that TMPRSS1‐null mice had no difference in the PPF area and the number of fibroblasts, while the number of muscle precursor cells was less than the wild type. These observations suggest that during early development, TMPRSS1 may play a role in maintaining the structure and function of the diaphragm and we would suggest that a genetic analysis of this modification be performed in patients with diaphragm elevation.