American journal of physiology. Lung cellular and molecular physiology
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jun 2018
Nintedanib reduces pulmonary fibrosis in a model of rheumatoid arthritis-associated interstitial lung disease.
Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) develops in ~20% of patients with RA. SKG mice, which are genetically prone to development of autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles human cellular and fibrotic nonspecific interstitial pneumonia. Nintedanib, a tyrosine kinase inhibitor approved for treatment of idiopathic pulmonary fibrosis, has been shown to reduce the decline in lung function. ⋯ Early intervention with nintedanib significantly reduced development of arthritis based on joint assessment and high-resolution μ-CT. This study impacts the RA and ILD fields by facilitating identification of a therapeutic treatment that may improve both diseases. As this model replicates the characteristics of RA-ILD, the results may be translatable to the human disease.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · May 2018
Pulmonary vascular dysfunction secondary to pulmonary arterial hypertension: insights gained through retrograde perfusion.
Here, we tested the hypothesis that severe pulmonary arterial hypertension impairs retrograde perfusion. To test this hypothesis, pulmonary arterial hypertension was induced in Fischer rats using a single injection of Sugen 5416 followed by 3 wk of exposure to 10% hypoxia and then 2 wk of normoxia. This Sugen 5416 and hypoxia regimen caused severe pulmonary arterial hypertension, with a Fulton index of 0.73 ± 0.07, reductions in both the pulmonary arterial acceleration time and pulmonary arterial acceleration to pulmonary arterial ejection times ratio, and extensive medial hypertrophy and occlusive neointimal lesions. ⋯ Retrograde perfusion was not rescued by maximal vasodilation. Retrograde perfusion was preserved in lungs from animals treated with Sugen 5416 and hypoxia for 1 and 3 wk, in lungs from animals with a milder form of hypoxic hypertension, and in normotensive lungs subjected to high outflow pressures. Thus impaired retrograde perfusion coincides with development of severe pulmonary arterial hypertension, with advanced structural defects in the microcirculation.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Apr 2018
Review Historical ArticlePersonalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations.
Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting ~1 in 3,500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, more than 2,000 CFTR mutations have been identified, which produce a wide range of phenotypes. ⋯ The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators' efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2018
Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. ⋯ CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2-/- mice but was attenuated in Tlr4-/- mice compared with CS-exposed WT controls. However, Tlr2-/- mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4-/- mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2018
Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition.
Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVECs from patients with IPAH and animals with experimental PH compared with normal controls. ⋯ EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48-72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.