American journal of physiology. Lung cellular and molecular physiology
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Aug 2009
Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury.
Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. ⋯ In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Aug 2009
Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus.
Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 +/- 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. ⋯ The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jul 2009
Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury.
Receptor for advanced glycation end-products (RAGE) is a marker of alveolar type I cells and is elevated in the pulmonary edema fluid of patients with acute lung injury (ALI). We tested the hypothesis that RAGE in the bronchoalveolar lavage (BAL) would be elevated in experimental models of direct ALI characterized by alveolar epithelial cell injury. We developed ELISA measurements for RAGE and studied ALI (direct and indirect) mouse models and collected BAL at specified endpoints to measure RAGE. ⋯ BAL RAGE did correlate with the severity of lung injury in acid and hyperoxia-induced ALI. In addition, with LPS-induced ALI, BAL RAGE was markedly reduced with MSC treatment. In summary, BAL RAGE is an indicator of ALI, and it may be useful in distinguishing direct from indirect models of ALI as well as assessing the response to specific therapies.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jun 2009
Lung environment determines unique phenotype of alveolar macrophages.
Alveolar macrophages (AM) are the most abundant antigen-presenting cells in the lungs, and they play a critical role in regulating pulmonary immune responses to inhaled pathogens and to allergens. However, compared with macrophages in other body sites, AM have an unusual phenotype that, in many respects, resembles the phenotype of dendritic cells (DC). Therefore, to more fully define the unique nature of AM, we compared the phenotype and function of AM with the phenotype and function of resident peritoneal lavage-derived macrophages (PLM). ⋯ Finally, GM-CSF(-/-) mice failed to develop CD11c(+) AM, but CD11c(+) AM were present in SP-D(-/-) mice. However, macrophages from GM-CSF(-/-) bone marrow could upregulate CD11c expression when transferred to the airways of wild-type mice. These results suggest that the airway environment promotes development of macrophages with unique DC-like characteristics and that this unusual phenotype is determined, to a large degree, by locally high concentrations of GM-CSF and, possibly, SP-D.
-
Am. J. Physiol. Lung Cell Mol. Physiol. · Jun 2009
Clinical TrialMass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis.
Exhaled breath condensate (EBC) analyses promise simple and noninvasive methods to measure airway biomarkers but pose considerable methodological challenges. We utilized mass spectrometry to measure EBC purine biomarkers adenosine and AMP plus urea to control for dilutional variability in two studies: 1) a cross-sectional analysis of 28 healthy, 40 cystic fibrosis (CF), and 11 asthmatic children; and 2) a longitudinal analysis of 26 CF children before and after treatment of a pulmonary exacerbation. EBC adenosine, AMP, and urea were readily detected and quantified by mass spectrometry, and analysis suggested significant dilutional variability. ⋯ Changes in EBC purine-to-urea ratios correlated with changes in percent predicted forced expiratory volume in 1 s (FEV(1)) (r = -0.53 AMP/urea, r = -0.55 adenosine/urea; P < 0.01 for both) after CF exacerbation treatment. Similar results were observed using dilution factors calculated from serum-to-EBC urea ratios or EBC electrolytes, and the comparable ratios of EBC electrolytes to urea in CF and control (median 3.2, IQR 1.6-6.0 CF; median 5.5, IQR 1.4-7.7 control) validated use of airway urea as an EBC dilution marker. These results show that mass spectrometric analyses can be applied to measurement of purines in EBC and demonstrate that EBC adenosine-to-urea and AMP-to-urea ratios are potential noninvasive biomarkers of airways disease.