Inter-α-Inhibitor Blocks Epithelial Sodium Channel Activation and Decreases Nasal Potential Differences in ΔF508 Mice

Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Inter-α-inhibitor (IαI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IαI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IαI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl− currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IαI in ATII cells were accompanied by increased levels of uncleaved (immature) surface α-ENaC. IαI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (∆F508), or CF transmembrane conductance regulator knockout mice with IαI for 3 hours decreased the open probability of their ENaC channels by 50%. ∆F508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IαI in their BALF. A single intranasal instillation of IαI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IαI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of ∆F508 mice

Leflunomide Prevents Alveolar Fluid Clearance Inhibition by Respiratory Syncytial Virus

Rationale: Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors

A critical review of the American Journal of Physiology-Lung Cellular and Molecular Physiology: 2012–2015

I have had the privilege of serving as Editor-in-Chief of the American Journal of Physiology: Lung Cellular and Molecular Physiology from 1/1/2012 to 1/1/2015 and have been reappointed for another 3-year term. When I took over as editor, I published an editorial in AJP-Lung in which I highlighted my vision and outlined the tasks to be accomplished to transform AJP-Lung into “The best place to publish basic, translational, and hypothesis-driven clinical lung research.” Herein I review our accomplishments during the first term. As promised, we review each article submitted to this journal and our reviews always help the quality and impact of every paper. We recognized the contributions of junior authors by establishing a number of awards and increased the visibility of AJP-Lung by establishing Facebook and Blog electronic pages and sponsoring symposia in scientific meetings. Our impact factor increased from 3.523 in 2011 to 4.041 in 2012 and, thanks to our calls for papers, we are receiving large numbers of high-quality papers in all aspects of pulmonary cell biology and lung diseases. The best is yet to come. </jats:p

<b>Global protein changes in the lungs of C57BL/6 mice exposed to air and injected with saline or human hemopexin.</b>

Proteomic analysis of lung samples of mice exposed to air, injected with a single injection of human hemopexin and sacrificed 24 h later</p

Supplemental Material for MSG L-00273-2023R1;Hemopexin Reverses Activation of Lung eIF2a and Decreases Mitochondrial Injury in Chlorine Exposed Mice

We assessed the mechanisms by which non-encapsulated heme, released in the plasma of mice post exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult male and female C57BL/6 mice to Cl2 (500 ppm for 30 min), returned them to room air, and injected them intramuscularly with either human hemopexin (hHPX; 5 µg/ g BW in 50 µl saline) or vehicle at 1h post exposure. Upon return to room air, Cl2 exposed mice, injected with vehicle, developed respiratory acidosis, increased concentrations of plasma proteins in the alveolar space, lung mitochondrial DNA injury, increased levels of free plasma heme and major alterations of their lung proteome. hHPX injection mice mitigated the onset and development of lung and mitochondrial injury and the increase of plasma heme, reversed the Cl2 induced changes in eighty-three of 237 proteins in the lung proteome at 24 h post exposure, andimproved survival at 15 d post-exposure.. System biology analysis of the lung global proteomics data showed that hHPX reversed changes of a number of key pathways including elF2 signaling, verified by western blotting measurements. Recombinant human hemopexin, generated in tobacco plants, injected at 1h post Cl2 exposure, was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2 results in acute lung injury and to the therapeutic effects of hemopexin</p

SUPPLEMENTAL MATERIAL_AJP Lung.docx

Herein we demonstrate that exposure of mice to chlorine gas causes significant changes in the lung proteome 24 h post exposure. System biology analysis of the proteomic data is consistent with damage to mitochondria and activation of eIF2, the master regulator of transcription and protein translation. Post exposure injection of hemopexin, which scavenges free heme, attenuated mtDNA injury, eIF2a phosphorylation, decreased lung injury and increased survival.</p