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Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease.

Am J Physiol Lung Cell Mol Physiol. 2015 Oct 2;:ajplung.00333.2015

Authors: Wagenaar GT, Hiemstra PS, Gosens R

Abstract
Supplemental oxygen after premature birth results in aberrant airway, alveolar and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia (BPD), and development of wheeze and asthma, pulmonary hypertension and COPD in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) signal transduction pathway has significant beneficial effects on disease development in animal models, so far this could not be translated to the clinic. Oxidative stress reduces the NO-sGC-cGMP pathway by oxidizing heme-bound sGC, resulting in inactivation or degradation of sGC. Reduced sGC activity and/or expression is associated with pathology due to premature birth, oxidative stress-induced lung injury, including impaired alveolar maturation, smooth muscle cell (SMC) proliferation and contraction, impaired airway relaxation and vasodilation, inflammation, pulmonary hypertension, right ventricular hypertrophy and an aggravated response towards hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca2+ responses were significantly elevated in hyperoxia-exposed fetal human airway SMC’s compared to normoxic controls, and that this hyperoxia-induced increase in the response was strongly reduced by NO-independent stimulation and activation of sGC. These recent studies highlight the therapeutic potential of sGC modulators in the treatment of preterm infants for respiratory distress with supplemental oxygen. Such treatment is aimed at improving aberrant alveolar and vascular development of the neonatal lung, and preventing the development of wheezing and asthma in survivors of premature birth. In addition, these studies highlight the suitability of fetal human airway SMC’s as a translational model for pathological airway changes in the neonate.

PMID: 26432873 [PubMed – as supplied by publisher]

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