American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Mar 2012
Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by receptor for advanced glycation end-products signaling.
The effects of acute hyperglycemia on lung ischemia-reperfusion (IR) injury and the role of receptor for advanced glycation end-products (RAGE) signaling in this process are unknown. The objective of this study was twofold: (1) evaluate the impact of acute hyperglycemia on lung IR injury; and (2) determine if RAGE signaling is a mechanism of hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism. ⋯ Lung injury and dysfunction after IR were attenuated in normoglycemic RAGE (-/-) mice, and hyperglycemia failed to exacerbate IR injury in RAGE (-/-) mice. Thus, this study demonstrates that acute hyperglycemia exacerbates lung IR injury, whereas RAGE deficiency attenuates IR injury and also prevents exacerbation of IR injury in an acute hyperglycemic setting. These results suggest that hyperglycemia-enhanced lung IR injury is mediated, at least in part, by RAGE signaling, and identifies RAGE as a potential, novel therapeutic target to prevent post-transplant lung IR injury.
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Am. J. Respir. Cell Mol. Biol. · Jan 2012
Eph-A2 promotes permeability and inflammatory responses to bleomycin-induced lung injury.
Stimulation by the ephrin-A1 ligand of the EphA2 receptor increases endothelial permeability. Lung injury increases the expression of EphA2, but the role of EphA2 in such injury is not well understood. To determine whether EphA2 contributes to changes in permeability and inflammation in the injured lung, we studied wild-type (WT) and EphA2 knockout (KO) mice, using isolated, perfused lung (IPL) preparations and a model of bleomycin-induced lung injury. ⋯ Because NF-κβ mediates the production of chemokines, the effect of the ephrin-A1 ligand on the activation of NF-κβ and the expression of chemokines was measured in endothelial cells. Ephrin-a1 significantly increased NF-κβ nuclear translocation and the expression of chemokine mRNA. This study demonstrates that the expression of EphA2 increases in the injured lung, and not only contributes to changes in permeability, but also plays a previously unrecognized role in promoting inflammatory responses.
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Am. J. Respir. Cell Mol. Biol. · Dec 2011
Gi-coupled γ-aminobutyric acid-B receptors cross-regulate phospholipase C and calcium in airway smooth muscle.
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system, and exerts its actions via both ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. Although the functional expression of GABA(B) receptors coupled to the G(i) protein was reported for airway smooth muscle, the role of GABA(B) receptors in airway responsiveness remains unclear. We investigated whether G(i)-coupled GABA(B) receptors cross-regulate phospholipase C (PLC), an enzyme classically regulated by G(q)-coupled receptors in human airway smooth muscle cells. ⋯ Moreover, baclofen potentiated the substance P-induced contraction of airway smooth muscle in isolated guinea pig tracheal rings. In conclusion, the stimulation of GABA(B) receptors in human airway smooth muscle cells rapidly mobilizes intracellular Ca(2+) stores by the synthesis of inositol phosphate via the activation of PLC-β, which is stimulated by G(βγ) protein liberated from G(i) proteins coupled to GABA(B) receptors. Furthermore, crosstalk between GABA(B) receptors and G(q)-coupled receptors potentiates the synthesis of inositol phosphate, transient increases in [Ca(2+)](i), and smooth muscle contraction through G(i) proteins.
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Am. J. Respir. Cell Mol. Biol. · Dec 2011
Multicenter Study Clinical TrialThe association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.
Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. ⋯ Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.
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Am. J. Respir. Cell Mol. Biol. · Dec 2011
ReviewEverything prevents emphysema: are animal models of cigarette smoke-induced chronic obstructive pulmonary disease any use?
There is a very large number of experimental approaches that prevent cigarette smoke-induced emphysema in laboratory animals, but the few similar treatments that have been tried in humans have had minimal effects, leading to questions of whether animal models of chronic obstructive pulmonary disease (COPD) are of any use in developing treatments for human disease. We review possible reasons for this problem. First, humans usually get treated when they have severe (Global Initiative for Chronic Obstructive Lung Disease III/IV) COPD, but animal models only produce mild (Global Initiative for Chronic Obstructive Lung Disease I/II) disease that never progresses after smoking cessation, and never develops spontaneous exacerbations (i.e., animal models are not models of severe human disease, and probably can't be used to model treatment of severe disease). ⋯ Third, animal models are typically Day 1 of smoke exposure "prevention" models, but humans are always treated well along in the course of their disease; thus, any human treatment will be an intervention, and not a prevention. We propose that animal models should examine both emphysema and small airway remodeling, and that experiments should include a relatively late intervention arm. This approach, combined with the realization that human COPD probably needs early rather than late treatment, may make development of treatments based on animal models more relevant.