American journal of respiratory cell and molecular biology
-
Am. J. Respir. Cell Mol. Biol. · Jun 2012
Immune responses in cystic fibrosis: are they intrinsically defective?
Cystic fibrosis (CF), the most common lethal single-gene disorder affecting Northern Europeans and North Americans, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cftr is a chloride channel and a regulator of other ion channels, and many aspects of the CF phenotype are directly related to ion channel abnormalities attributable to CFTR mutation. Lung disease is the most common limitation to the quantity and quality of life for patients with CF. ⋯ Defective CFTR function disrupts the balance of intracellular ion concentrations, including [Ca(2+)], which is known to drive gene expression pathways. New evidence links this hypothesis to anomalies in immune activation observed across CF cell types, which could shed light on the inability of individuals with CF to effectively clear pathogens. This review focuses on the emerging role of Cftr in gene expression and other functions in cells of the innate and adaptive immune system.
-
Am. J. Respir. Cell Mol. Biol. · May 2012
Prenatal nicotine exposure alters lung function and airway geometry through α7 nicotinic receptors.
Maternal smoking during pregnancy has been associated with adverse effects on respiratory health. Whereas the epidemiologic link is incontrovertible, the mechanisms responsible for this association are still poorly understood. Although cigarette smoke has many toxic constituents, nicotine, the major addictive component in cigarette smoke, may play a more significant role than previously realized. ⋯ In addition, adult mice exposed to prenatal nicotine exhibit an increased response to methacholine challenge, even in the absence of allergic sensitization. Collagen expression was increased between adjacent airways and vessels, which was absent in α7 nAChR knockout mice. These observations provide a unified mechanism of how maternal smoking during pregnancy may lead to lifelong alterations in offspring pulmonary function and increased risk of asthma, and suggest potential targets to counteract those effects.
-
Am. J. Respir. Cell Mol. Biol. · May 2012
Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal form of interstitial lung disease (ILD). The precise molecular mechanisms of IPF remain poorly understood. However, analyses of mice receiving bleomycin (BLM) as a model of IPF established the importance of preceding inflammation for the formation of fibrosis. ⋯ In addition, we confirmed that periostin is highly expressed in the lung tissue of chemotherapeutic-agent-induced ILD as well as of patients with IPF. Taking these results together, we conclude that periostin plays a unique role as an inducer of chemokines to recruit neutrophils and macrophages important in the process of pulmonary fibrosis in BLM-administered model mice. Our results suggest a therapeutic potential for periostin in IPF and drug-induced ILD.
-
Am. J. Respir. Cell Mol. Biol. · Apr 2012
Hypoxia-induced pulmonary arterial smooth muscle cell proliferation is controlled by forkhead box M1.
Pulmonary arterial hypertension (PAH) is a devastating disease, and no effective treatments are available. Hypoxia-induced pulmonary artery remodeling, including smooth muscle cell proliferation, contributes to PAH, but the exact mechanisms underlying this abnormal process are largely undefined. The forkhead box M1 (FoxM1) transcription factor regulates cancer cell growth by modulating gene expression critical for cell cycle progression. ⋯ However, the knockdown of FoxM1 did not alter expression levels of HIF-2α or HIF-1α, suggesting that HIF-2α is an upstream regulator of FoxM1. Furthermore, the knockdown of FoxM1 prevented the hypoxia-induced expression of aurora A kinase and cyclin D1. Collectively, our results suggest that hypoxia induces FoxM1 gene expression in an HIF-2α-dependent pathway, thereby promoting HPASMC proliferation.
-
Am. J. Respir. Cell Mol. Biol. · Apr 2012
Retracted PublicationMaternal diesel inhalation increases airway hyperreactivity in ozone-exposed offspring.
Air pollutant exposure is linked with childhood asthma incidence and exacerbations, and maternal exposure to airborne pollutants during pregnancy increases airway hyperreactivity (AHR) in offspring. To determine if exposure to diesel exhaust (DE) during pregnancy worsened postnatal ozone-induced AHR, timed pregnant C57BL/6 mice were exposed to DE (0.5 or 2.0 mg/m(3)) 4 hours daily from Gestation Day 9-17, or received twice-weekly oropharyngeal aspirations of the collected DE particles (DEPs). Placentas and fetal lungs were harvested on Gestation Day 18 for cytokine analysis. ⋯ Mice born to the high-concentration diesel-exposed dams had worse ozone-induced AHR, which persisted in the 4-week recovery animals. Prenatal diesel exposure combined with postnatal ozone exposure also worsened secondary alveolar crest development. We conclude that maternal inhalation of DE in pregnancy provokes a fetal inflammatory response that, combined with postnatal ozone exposure, impairs alveolar development, and causes a more severe and long-lasting AHR to ozone exposure.