Systemic hydrogen sulfide administration partially restores normal alveolarization in an experimental animal model of bronchopulmonary dysplasia

Abstract

Arrested alveolarization is the pathological hallmark of bronchopulmonary dysplasia (BPD), a complication of premature birth. Here, the impact of systemic application of hydrogen sulfide (H2S) on postnatal alveolarization was assessed in a mouse BPD model. Exposure of newborn mice to 85% O2 for 10 days reduced the total lung alveoli number by 56% and increased alveolar septal wall thickness by 29%, as assessed by state-of-the-art stereological analysis. Systemic application of H2S via the slow-release H2S donor GYY4137 for 10 days resulted in pronounced improvement in lung alveolarization in pups breathing 85% O2, compared with vehicle-treated littermates. Although without impact on lung oxidative status, systemic H2S blunted leukocyte infiltration into alveolar air spaces provoked by hyperoxia, and restored normal lung interleukin 10 levels that were otherwise depressed by 85% O2. Treatment of primary mouse alveolar type II (ATII) cells with the rapid-release H2S donor NaHS had no impact on cell viability; however, NaHS promoted ATII cell migration. Although exposure of ATII cells to 85% O2 caused dramatic changes in mRNA expression, exposure to either GYY4137 or NaHS had no impact on ATII cell mRNA expression, as assessed by microarray, suggesting that the effects observed were independent of changes in gene expression. The impact of NaHS on ATII cell migration was attenuated by glibenclamide, implicating ion channels, and was accompanied by activation of Akt, hinting at two possible mechanisms of H2S action. These data support further investigation of H2S as a candidate interventional strategy to limit the arrested alveolarization associated with BPD.

A review of recent developments and applications of morphometry/stereology in lung research

“…However, this complex pathology does not have a long tradition of state-of-the-art stereology, which explains why most authors resorted to less suitable and less reliable morphometric methods. In that respect, it is worth mentioning the article by Madurga et al (83). Here, the authors used a mouse model of BPD induced by hyperoxia to investigate the effect of systemic hydrogen sulfide administration on alveolarization.…”

“…For several of these diseases, a set of wellsuited stereological parameters has been available for a long time, such as acute lung injury (103,112) and emphysema (113). In other cases, the application of stereology is just emerging such as fibrosis (9, 82) or bronchopulmonary dysplasia (83). In pulmonary hypertension, various morphometric methods have been used since many years which relate to the thickness of the vessel media (%medial thickness) and the amount of non-, partially, or fully muscularized vessels.…”

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption

“…H 2 S might, thus, contribute to hypoxic inhibition of sodium transport in pulmonary epithelial cells (35,47,65,77,82). 2) In low concentrations, H 2 S exerts anti-inflammatory, anti-oxidant, and vasoactive properties and is currently being evaluated as a potential therapeutic option in animal models of various lung diseases (15,49,81), including acute lung injury (ALI) (25-27, 29, 64). Most of those studies investigated effects upon systemic administration of H 2 S-liberating molecules or sulfur salts, such as Na 2 S/NaHS.…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…In a recent report, GYY4137 coadministered with histamine into mouse skin inhibited the accompanying pruritis but did not affect the extravasations response (Rodrigues et al, 2013) again suggesting differences in the response to GYY4137 in different systems. Finally, administration of GYY4137 to newborn mouse pups subjected to hyperoxia (85% O 2 for 10 days) augmented lung alveoli development whilst blunting leuokocyte infiltration into the alveolar spaces indicative of an overall anti-inflammatory effect (Madurga et al, 2014). Cumulatively, these studies show that GYY4137 consistently reduces the expression and/or generation of proinflammatory mediators in vitro but has a more complex pattern of effects in animal models of inflammation in vivo.…”