Abstract
BackgroundIn extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development.MethodsRat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry.ResultsPostnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation.ConclusionPostnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.
Highlights
Pulmonary hypertension (PH) is an increase in pulmonary vascular resistance resulting in a decrease in pulmonary blood flow and right ventricular hypertrophy (RVH)
To determine if activation of Toll-like receptor 4 (TLR4) by Enterobacteriaceae is involved in the development of PH in these rats, we first determined the efficacy of the TLR4 antagonist TAK-242 to attenuate PH
Treatment with TAK-242 attenuated RVH in pups exposed to postnatal growth restriction (PNGR) with and without hyperoxia, but not in pups exposed to hyperoxia alone (Figure 1A)
Summary
Pulmonary hypertension (PH) is an increase in pulmonary vascular resistance resulting in a decrease in pulmonary blood flow and right ventricular hypertrophy (RVH). TLR4 and the Gut-Lung Axis disease [1, 2] In this population, PH is associated with very high morbidity and 50% mortality [3]. In a recent prospective study of PH, among extremely preterm infants with BPD (mean gestational age at birth 26 weeks) evaluated at 36 to 38 weeks corrected gestational age, 13/44 (30%) patients with PH had a history of NEC, while only 8/115 (7%) patients without PH had a history of NEC [adjusted odds ratio 5.5 (95% confidence intervals 1.9, 15.4)] [9], suggesting an association between inflammation in the gut and pulmonary vascular disease. Postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development
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