Resp Res
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Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers. ⋯ This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.
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Comparative Study
Krüppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis. ⋯ We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.
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Case Reports
Altered surfactant homeostasis and recurrent respiratory failure secondary to TTF-1 nuclear targeting defect.
Mutations of genes affecting surfactant homeostasis, such as SFTPB, SFTPC and ABCA3, lead to diffuse lung disease in neonates and children. Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription factor-1 (TTF-1)--critical for lung, thyroid and central nervous system morphogenesis and function--causes a rare form of progressive respiratory failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in this syndrome are heterogeneous and poorly explored. We report a novel TTF-1 molecular defect causing recurrent respiratory failure episodes in an infant. ⋯ Defective TTF-1 signaling may result in profound surfactant homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous ABCA3 missense mutations may act as disease modifiers in other genetic surfactant defects.
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Comparative Study
Profibrotic potential of prominin-1+ epithelial progenitor cells in pulmonary fibrosis.
In idiopathic pulmonary fibrosis loss of alveolar epithelium induces inflammation of the pulmonary tissue followed by accumulation of pathogenic myofibroblasts leading eventually to respiratory failures. In animal models inflammatory and resident cells have been demonstrated to contribute to pulmonary fibrosis. Regenerative potential of pulmonary and extra-pulmonary stem and progenitor cells raised the hope for successful treatment option against pulmonary fibrosis. Herein, we addressed the contribution of lung microenvironment and prominin-1(+) bone marrow-derived epithelial progenitor cells in the mouse model of bleomycin-induced experimental pulmonary fibrosis. ⋯ The microenvironment of inflamed lung impairs the regenerative capacity of bone marrow-derived prominin-1(+) progenitors and promotes their differentiation into pathogenic phenotypes.
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KL-6 is a mucin-like glycoprotein expressed on the surface of alveolar type II cells. Elevated concentrations of KL-6 in serum and epithelial lining fluid (ELF) in patients with acute respiratory distress syndrome (ARDS) have been previously reported; however, kinetics and prognostic significance of KL-6 have not been extensively studied. This study was conducted to clarify these points in ARDS patients. ⋯ ELF and serum KL-6 concentrations were found to be good indicators of clinical outcome in ARDS patients. Particularly, KL-6 levels in ELF measured during the early period after the diagnosis were useful for predicting prognosis in ARDS patients.