Strain-dependent effects on lung structure, matrix remodeling, and Stat3/Smad2 signaling in C57BL/6N and C57BL/6J mice after neonatal hyperoxia

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants, characterized by lung growth arrest and matrix remodeling. Various animal models provide mechanistic insights in the pathogenesis of BPD. Since there is increasing evidence that genetic susceptibility modifies the response to lung injury, we investigated strain-dependent effects in hyperoxia (HYX)-induced lung injury of newborn mice. To this end, we exposed newborn C57BL/6N and C57BL/6J mice to 85% O2 (HYX) or normoxia (NOX; 21% O2) for 28 days, followed by lung excision for histological and molecular measurements. BL/6J-NOX mice exhibited a lower body and lung weight than BL/6N-NOX mice; hyperoxia reduced body weight in both strains and increased lung weight only in BL/6J-HYX mice. Quantitative histomorphometric analyses revealed reduced alveolar formation in lungs of both strains after HYX, but the effect was greater in BL/6J-HYX mice than BL/6N-HYX mice. Septal thickness was lower in BL/6J-NOX mice than BL/6N-NOX mice but increased in both strains after HYX. Elastic fiber density was significantly greater in BL/6J-HYX mice than BL/6N-HYX mice. Lungs of BL/6J-HYX mice were protected from changes in gene expression of fibrillin-1, fibrillin-2, fibulin-4, fibulin-5, and surfactant proteins seen in BL/6N-HYX mice. Finally, Stat3 was activated by HYX in both strains; in contrast, activation of Smad2 was markedly greater in lungs of BL/6N mice than BL/6J mice after HYX. In summary, we demonstrate strain-dependent differences in lung structure and matrix, alveolar epithelial cell markers, and Smad2 (transforming growth factor β) signaling in neonatal HYX-induced lung injury. Strain-dependent effects and genetic susceptibility need be taken into consideration for reproducibility and reliability of results in animal models.

Predicting Hyperoxia-Induced Lung Injury from Associated Intestinal and Lung Dysbiosis in Neonatal Mice

“…On postnatal day 7, we observed that mice reared in hyperoxia exhibited signi cantly lower body weights than did those reared in RA. These results are compatible with those of another study that found hyperoxia to reduce body weight in C57BL/6N mice [21]. In our other studies, we have demonstrated that hyperoxia exposure during the rst 7 days of life induces lung injury, reduces alveolarization and angiogenesis, injures the distal small intestine, disrupts the intestinal barrier, and impairs intestinal function in newborn Sprague Dawley rats [22,23].…”

Pulmonary mechanics and structural lung development after neonatal hyperoxia in mice

“…One limitation is that this study only used C57BL/6J mice, and mouse strain is an important factor in oxygen sensitivity and airway responses. We chose this strain because it is the most sensitive to hyperoxia-induced perturbations in alveolar development but other strains (BALB/c) are commonly utilized for AHR models, especially in asthma (50,51). We also did not look at other intrapulmonary and extrapulmonary processes that are effected by hyperoxia that we speculate do not relate to pulmonary mechanics.…”

Of Mice and Men: The Coronavirus MHV and Mouse Models as a Translational Approach to Understand SARS-CoV-2

“…Work with MHV only requires biosafety level 2 containment as opposed to biosafety level 3 containment when working with SARS-CoV and SARS-CoV-2. Interestingly, even though some coronaviruses are antigenically closely related they are biologically different [30], and pulmonary response in mice is mouse and virus strain-dependent [145,146]. Intranasal inoculation of BALB/c mice with MHV-3, MHV-A59, MHV-1, MHV-S, and MHV-JHM revealed that MHV-1, which is primarily pneumovirulent, produced a transient lung pathology most similar to SARS, which completely resolved by day 21.…”