Effects of chronic neonatal hyperoxia-induced bronchopulmonary dysplasia on breathing, energy expenditure, and growth in young, adolescent, and adult mice

Abstract

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease associated with preterm birth. Growth failure is common in infants with BPD and is associated with increased resting metabolic rate (RMR). Whether increased RMR and growth failure are a consequence of BPD lung pathology per se, or a consequence of clinical interventions remains unknown. Herein, we sought to determine the effects of BPD-like lung injury on breathing, growth, and energy expenditure in C57BL/6J male mice exposed to chronic hyperoxia (Hx; 70% O2; n=5) or normoxia (Nx; n=6) in the neonatal period (postnatal day (P) 0-14). Consistent with prior reports and human BPD, Hx lungs at P21 had reduced alveoli and alveolar density indicated via H&E lung sections. Also, Hx mice had altered respiratory responses to acute hypoxia (10 min; 12% O2) including a reduced hypoxic ventilatory response (108±6 Nx vs 89±4 % Hx; p<0.05) and drive to breathe (tidal volume/inspiratory time; 0.98±0.06 vs 0.76±0.04; p<0.05). The pattern of breathing during the acute challenge favors longer inspiratory time (132±6 vs 170±9 ms, p<0.05) which may reflect a compensatory response to reduced alveoli. Despite these differences, no differences in body composition (body, fat and fat-free masses, and total body water) were observed at P21, 6wks, or 8wks of life. Furthermore, there were no differences in ingestive behaviors, or total or resting aerobic heat production (kcal/h) at 8 wks of age, yet Hx mice had reduced locomotor activity (199±10 vs 154±11 m/d; p<0.05) which may indicate reduced exercise capacity. In a subset of mice (n=2/group), a 20% increase in right ventricular mass was noted, consistent with some degree of pulmonary hypertension, along with a 3% decrease in hematocrit, which may reflect a programmed change in hematopoiesis after early-life Hx. Together, these data document the impact of BPD-like lung injury on key physiological parameters and support the iconoclastic concept that BPD pathology per se does not drive increased RMR or growth failure. By extension, other factors – possibly including side-effects of well-intentioned clinical interventions – may underly growth failure in children with BPD. We speculate that sodium depletion resulting from diuretic therapy, which is common for this condition and known to impact infant growth, may be an important contributor to growth failure in infants with BPD. GCM: AHA 20CDA35310121; JLG: DK133121, HL134850, and HL084207; JLS: DK133121 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.