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

Abstract

Wagenaar GT, Hiemstra PS, Gosens R. Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 309: L1037-L1040, 2015. First published October 2, 2015; doi:10.1152/ajplung.00333.2015.-Supplemental oxygen after premature birth results in aberrant airway, alveolar, and pulmonary vascular development with an increased risk for bronchopulmonary dysplasia, and development of wheeze and asthma, pulmonary hypertension, and chronic obstructive pulmonary disease in survivors. Although stimulation of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-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 toward hyperoxia-induced neonatal lung injury. Recently, Britt et al. (10) demonstrated that histamine-induced Ca 2ϩ responses were significantly elevated in hyperoxia-exposed fetal human airway SMCs compared with 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 SMCs as a translational model for pathological airway changes in the neonate.airway remodeling, calcium response; fetal human airway smooth muscle cells; hyperoxia; oxidative stress; nitric oxide; soluble guanylate cyclase; guanosine 3=, 5=-cyclic monophosphate TREATMENT OF RESPIRATORY DISTRESS after premature birth with supplemental oxygen may interfere with the development of the immature lung, resulting in aberrant airway, alveolar, and vascular development. Survivors of premature birth are at risk for developing pulmonary arterial hypertension, recurrent wheeze and asthma, and chronic obstructive pulmonary disease (COPD) at relatively young ages (3,6,17,21,34). The underlying pathology has a multifactorial etiology, and the NO-soluble guanylate cyclase (sGC)-cGMP pathway is involved in many factors that contribute to it. Nitric oxide (NO) is a key signaling molecule in many biological and physiological processes, regulating cell growth, differentiation, proliferation, smooth muscle r...

Functional Cooperation between KCa3.1 and TRPV4 Channels in Bronchial Smooth Muscle Cell Proliferation Associated with Chronic Asthma

“…Chronic asthma is an inflammatory airway disorder characterized by AHR and airway remodeling ( Lim et al, 2017 ). Increased mucous gland hyperplasia, extracellular matrix deposition, and the proliferation of airway SMC may result in lung function decline ( Wagenaar et al, 2015 ). Increased bulk of HBSM plays an important role in airway remodeling derived from subjects with asthma.…”

Vascular and pulmonary effects of ibuprofen on neonatal lung development

“…Alternatively, the beneficial effect on vascular remodeling can also be mediated via ibuprofen's offtarget effect of elevating intracellular cGMP levels via cGMP-selective phosphodiesterase (PDE) inhibition [54,55]. This explanation is supported by the beneficial effects of agents that increase intracellular cGMP levels, either by stimulating the NO-eNOS-cGMP pathway with inhaled NO, apelin or soluble guanylate cyclase modulators or inhibiting cGMP breakdown with the specific cGMP-selective PDE5 inhibitor sildenafil, in newborn rats with experimental BPD that our group and others described previously [9,50,[56][57][58]. Interestingly, the beneficial effects of ibuprofen on experimental BPD may be explained by activation of the apelin/APJ pathway, which we have demonstrated to protect against experimental BPD in rats [9].…”

Altered vasoreactivity in neonatal rats with pulmonary hypertension associated with bronchopulmonary dysplasia: Implication of both eNOS phosphorylation and calcium signaling

“…This study provides the first evidence that Ca 2+ signaling is modified in PASMC from newborn rat with BPD-PH. Interestingly, Ca 2+ signaling in PASMC plays a central role both in vasoconstriction, through its pivotal effect on PASMC contraction, and in vascular remodeling, through its stimulatory effect on PASMC proliferation and migration [ 32 , 33 ]. We demonstrated that the resting [Ca 2+ ] cyt is higher in the PASMC from hyperoxic newborn rats than in those from controls.…”