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Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

ABSTRACT: Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl(2) dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl(2) (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (? 60%) in aorta isolated from Cl(2)-exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl(2) exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl(2)-exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl(2) exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.

SUBMITTER: Honavar J

PROVIDER: S-EPMC3175567 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other

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Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

Honavar Jaideep J Samal Andrey A AA Bradley Kelley M KM Brandon Angela A Balanay Joann J Squadrito Giuseppe L GL MohanKumar Krishnan K Maheshwari Akhil A Postlethwait Edward M EM Matalon Sadis S Patel Rakesh P RP

American journal of respiratory cell and molecular biology 20101203 2

Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS ...[more]

PMID: 21131444

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Project description:BackgroundThe mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear. Recent work has established the existence of an indirect process by which factors released from the lung into the circulation promote systemic inflammation and cellular dysfunction, particularly on the vasculature. However, the composition of circulating contributing factors and how they are produced remains unknown. Evidence suggests matrix protease involvement; thus, here we used a well-characterized multi-walled carbon nanotube (MWCNT) oropharyngeal aspiration model with known vascular effects to assess the distinct contribution of nanoparticle-induced peptide fragments in driving systemic pathobiology.ResultsData-independent mass spectrometry enabled the unbiased quantitative characterization of 841 significant MWCNT-responses within an enriched peptide fraction, with 567 of these factors demonstrating significant correlation across animal-paired bronchoalveolar lavage and serum biofluids. A database search curated for known matrix protease substrates and predicted signaling motifs enabled identification of 73 MWCNT-responsive peptides, which were significantly associated with an abnormal cardiovascular phenotype, extracellular matrix organization, immune-inflammatory processes, cell receptor signaling, and a MWCNT-altered serum exosome population. Production of a diverse peptidomic response was supported by a wide number of upregulated matrix and lysosomal proteases in the lung after MWCNT exposure. The peptide fraction was then found bioactive, producing endothelial cell inflammation and vascular dysfunction ex vivo akin to that induced with whole serum. Results implicate receptor ligand functionality in driving systemic effects, exemplified by an identified 59-mer thrombospondin fragment, replete with CD36 modulatory motifs, that when synthesized produced an anti-angiogenic response in vitro matching that of the peptide fraction. Other identified peptides point to integrin ligand functionality and more broadly to a diversity of receptor-mediated bioactivity induced by the peptidomic response to nanoparticle exposure.ConclusionThe present study demonstrates that pulmonary-sequestered nanoparticles, such as multi-walled carbon nanotubes, acutely upregulate a diverse profile of matrix proteases, and induce a complex peptidomic response across lung and blood compartments. The serum peptide fraction, having cell-surface receptor ligand properties, conveys peripheral bioactivity in promoting endothelial cell inflammation, vasodilatory dysfunction and inhibiting angiogenesis. Results here establish peptide fragments as indirect, non-cytokine mediators and putative biomarkers of systemic health outcomes from nanoparticle exposure.

Dataset Information

Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

Publications

Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

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