Chronic hypercapnia alters lung matrix composition in mouse pups
Abstract Rationale: Permissive hypercapnia, a stretch-limiting ventilation strategy, often results in high PaCO2. This strategy is associated with reduced morbidity and mortality in premature infants and its benefits have been attributed to diminished barotrauma. However, little is known about the independent effect of high CO2levels during the lung development. Methods: Mice were exposed to 8% CO2 or room air for 2 weeks either from postnatal day 2 through 17 or as adults (~2 months of age). Lungs were excised and processed for protein, RNA, histology and total lung volumes. Results: Histologic analysis demonstrated that alveolar walls of CO2-exposed mouse pups were thinner than those of controls and had twice the total lung volume. Molecular analysis revealed that several matrix proteins in the lung were down-regulated in mouse pups exposed to hypercapnia. Interstitial collagen type I α1, type III α1, elastin and fibronectin protein and mRNA levels were less than half of controls while collagen IV α5 was unaffected. This decrease in interstitial collagen could thus account for the thinning of the interstitial matrix and the altered lung biomechanics. Matrix metalloproteinase (MMP) -8, a collagenase that has specificity for collagen types I and III, increased in hypercapnic mouse pups suggesting increased collagen degradation. Moreover, tissue inhibitor of MMP (TIMP) -1, a potent inhibitor of MMP-8, was significantly decreased. However, unlike pups, adult mice exposed to hypercapnia demonstrated only a mild increase in total lung volumes and did not exhibit similar molecular or histologic changes. Conclusions: Although permissive hypercapnia may prevent lung injury from barotrauma, our study revealed that exposure to hypercapnia may be an important factor in lung remodeling and function, especially in early life.