title: Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease.
abstract: 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(2+) 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.
authors.affiliation: Laboratory of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands; g.t.m.wagenaar@lumc.nl.
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands; and.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.affiliation: Department of Molecular Pharmacology and Groningen Research Institute for Asthma and Chronic Obstructive Pulmonary Disease, University of Groningen, Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology; D020536:Enzyme Activators / Q000494:pharmacology* / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000502:physiology*; D006801:Humans; D058990:Molecular Targeted Therapy; D010102:Oxygen Inhalation Therapy / Q000009:adverse effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy* / Q000201:enzymology; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: airway remodeling, calcium response; fetal human airway smooth muscle cells; guanosine 3′, 5′-cyclic monophosphate; hyperoxia; nitric oxide; oxidative stress; soluble guanylate cyclase