American journal of physiology. Lung cellular and molecular physiology
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Am. J. Physiol. Lung Cell Mol. Physiol. · Mar 2010
Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory infiltration of leukocytes, lung injury induced by reactive oxygen species (ROS), in particular superoxide anion, and fibrosis (collagen deposition). No treatment has been shown to improve definitively the prognosis for IPF patients. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. ⋯ Intratracheal administration or inhalation of PC-SOD also attenuated the bleomycin-induced inflammatory response and fibrosis. The bell-shaped dose-response profile of PC-SOD was not observed for these routes of administration. We consider that, compared with intravenous administration, inhalation of PC-SOD may be a more therapeutically beneficial route of administration due to the higher safety and quality of life of the patient treated with this drug.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Mar 2010
Respiratory syncytial virus induces airway insensitivity to beta-agonists in BALB/c mice.
beta-Adrenergic agonists (beta-agonists) are commonly used to treat respiratory syncytial virus (RSV) bronchiolitis but are generally ineffective for unknown reasons. We have previously shown that RSV strain A2 inhibits bronchoalveolar epithelial responses to beta-agonists in a BALB/c mouse model by inducing heterologous keratinocyte cytokine (KC)/CXCR2-mediated desensitization of epithelial beta(2)-adrenergic receptors. The aim of the current study was to determine whether RSV also induces airway insensitivity to beta-agonists. ⋯ Terbutaline insensitivity at 2 d.p.i. could be reversed by systemic preinfection treatment with neutralizing anti-CXCR2 antibodies, which reduced bronchoalveolar lavage (BAL) neutrophil counts but did not alter viral replication, BAL KC levels, or lung edema. Terbutaline insensitivity was also reversed by postinfection nebulization with neutralizing anti-KC or anti-CXCR2 antibodies and could be replicated in normal, uninfected mice by nebulization with recombinant KC. These data suggest that KC/CXCR2-mediated airway insensitivity to beta-agonists may underlie the modest utility of these drugs as bronchodilators in therapy for acute RSV bronchiolitis.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Feb 2010
Targeted disruption of NF-{kappa}B1 (p50) augments cigarette smoke-induced lung inflammation and emphysema in mice: a critical role of p50 in chromatin remodeling.
NF-kappaB-mediated proinflammatory response to cigarette smoke (CS) plays a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The heterodimer of RelA/p65-p50 (subunits of NF-kappaB) is involved in transactivation of NF-kappaB-dependent genes, but interestingly p50 has no transactivation domain. The endogenous role of p50 subunit, particularly in regulation of CS-mediated inflammation in vivo, is not known. ⋯ Importantly, p50 deficiency resulted in increased phosphorylation (Ser276 and Ser536), acetylation (Lys310), and DNA binding activity of RelA/p65 in mouse lung, associated with increased chromatin remodeling evidenced by specific phosphoacetylation of histone H3 (Ser10/Lys9) and acetylation of H4 (Lys12) in response to CS exposure. Surprisingly, p50-null mice showed spontaneous air space enlargement, which was further increased after CS exposure compared with WT mice. Thus our data showed that p50 endogenously regulates the activity of RelA/p65 by decreasing its phosphoacetylation and DNA binding activity and specific histone modifications and that genetic ablation of p50 leads to air space enlargement in mouse.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Jan 2010
Long-term terbutaline exposure stimulates alpha1-Na+-K+-ATPase expression at posttranscriptional level in rat fetal distal lung epithelial cells.
Transepithelial Na(+) transport through epithelial Na(+) channels (ENaC) on the apical membrane and Na(+)-K(+)-ATPase activity on the basolateral membrane of distal lung epithelial cells are critical for alveolar fluid clearance. Acute exposure to beta-adrenergic agonists stimulates lung fluid clearance by increasing Na(+) transport. We investigated the effects of chronic exposure to the beta(2)-adrenergic agonist terbutaline on the transepithelial Na(+) transport in rat fetal distal lung epithelia (FDLE). ⋯ Terbutaline treatment did not affect alpha-, beta-, or gamma-ENaC mRNA or alpha-ENaC protein steady-state levels, but increased total cellular levels and rate of synthesis of alpha(1)-Na(+)-K(+)-ATPase protein in FDLE in the absence of any change in alpha(1)-Na(+)-K(+)-ATPase mRNA. Total cellular beta(1)-Na(+)-K(+)-ATPase mRNA and protein levels were not affected by terbutaline. These data suggest that FDLE have different responses from adult type II epithelial cells when chronically exposed to terbutaline, and their increased transepithelial Na(+) transport occurs via a posttranscriptional increase in alpha(1)-Na(+)-K(+)-ATPase expression.
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Am. J. Physiol. Lung Cell Mol. Physiol. · Dec 2009
Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome.
Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. ⋯ These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.