Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. This study was conducted to test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification—indicative of mitochondrial dysfunction and increased oxidant stress—when compared to MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicating that these cells had decreased mitophagy. Finally, these MSCs were also noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.
CONTEXT: Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting preterm infants. Studies implicate viral infections in etiopathogenesis. OBJECTIVE: To summarize the association of viral infections with NEC by systematic review and meta-analysis. DATA SOURCES: We searched Ovid-Medline, Embase, Web of Science, and Cochrane databases in November 2022. STUDY SELECTION: We included observational studies that examined the association between viral infections and NEC in newborn infants. DATA EXTRACTION: We extracted data regarding the methodology, participant characteristics, and outcome measures. RESULTS: We included 29 and 24 studies in the qualitative review and meta-analysis, respectively. The meta-analysis demonstrated a significant association between viral infections and NEC (odds ratio [OR], 3.81, 95% confidence interval: 1.99–7.30, 24 studies). The association remained significant after excluding the outliers (OR, 2.89 [1.56–5.36], 22 studies) and studies with poor methodology (OR, 3.33 [1.73–6.43], 22 studies). In subgroup analysis based on participants' birth weight, studies including very low birth weight infants only (OR, 3.62 [1.63–8.03], 8 studies) and non-very low birth weight infants only (OR, 5.28 [1.69–16.54], 6 studies) showed a significant association. In subgroup analysis based on specific viruses, infection with rotavirus (OR, 3.96 [1.12–13.95], 10 studies), cytomegalovirus (OR, 3.50 [1.60–7.65], 5 studies), norovirus (OR, 11.95 [2.05–69.84], 2 studies), and astrovirus (OR, 6.32 [2.49–16.02], 2 studies) was significantly associated with NEC. LIMITATIONS: Heterogeneity of the included studies. CONCLUSIONS: Viral infection is associated with an increased risk of NEC in newborn infants. We need methodologically sound prospective studies to assess the effect of preventing or treating viral infections on NEC incidence.
Mitochondrial dysfunction at birth predicts bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Recently, nebulized thyroid hormone (TH), given as triiodothyronine (T3) was noted to decrease pulmonary fibrosis in adult animals through improved mitochondrial function. In this study we tested the hypothesis that TH may have similar effects on hyperoxia-induced neonatal lung injury and mitochondrial dysfunction by testing whether intranasal T3 decreases neonatal hyperoxic lung injury in newborn mice, T3 improves mitochondrial function in lung homogenates, neonatal murine lung fibroblasts (NMLF) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) obtained from ELBW infants, and whether neonatal hypothyroxinemia is associated with BPD in ELBW infants. We found that Inhaled T3 (given intranasally) attenuated hyperoxiainduced lung injury and mitochondrial dysfunction in newborn mice. T3 also reduced bioenergetic deficits in UC-MSCs obtained both from infants with no/mild BPD and those with moderate/severe BPD. T3 also increased PGC1-α content in lung homogenates of mice exposed to hyperoxia as well as mitochondrial potential in both NMLF and UC-MSCs.ELBW infants who died or developed moderate/severe BPD had lower TT4 compared to survivors with no/mild BPD. In conclusion, TH signaling and function may play a critical role in neonatal lung injury and inhaled T3 supplementation may be useful as a therapeutic strategy for BPD.
Rationale: Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. Objective: To test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Findings: Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification - indicative of mitochondrial dysfunction and increased oxidant stress vs. MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicative of decreased mitophagy. Finally, these MSCs were noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. Conclusions: These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.
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