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Abstract: Transforming growth factor-β (TGFβ) is synthesized as a precursor protein, pro-TGFβ, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of [...]

Epithelial mucous membranes are repeatedly exposed to oxidants and xenobiotics. CFTR plays a role in glutathione transepithelial flux and in defining the hydration and viscoelasticity of protective mucus. We therefore hypothesized that CFTR expression and function may be modulated by oxidant stress. A sublethal oxidant stress (tert-butylhydroquinone, BHQ) in CFTR-expressing epithelial cells (T84) induced a significant increase in cellular glutathione that was associated with an increase in expression of the gene encoding the heavy subunit of the rate-limiting enzyme for glutathione synthesis, [gamma]-glutamylcysteine synthetase ([gamma]-GCShs). CFTR gene expression was markedly decreased according to a time course that mirrored the changes in [gamma]-GCShs. Western blot analysis confirmed that the decrease in CFTR gene expression was associated with a decrease in CFTR protein. cAMP-dependent iodide efflux was also decreased by the oxidant stress. Nuclear run-on assays indicated that the oxidant stress had no effect on CFTR gene transcription, but the mRNA stability in the oxidant-stressed cells was markedly reduced. Furthermore, BHQ increased [gamma]-GCShs mRNA while decreasing CFTR mRNA in Calu-3 cells, and taurine chloramine induced similar effects in T84 cells. We conclude that suppression of CFTR expression may represent an adaptive response of mucosal epithelium to an exogenous oxidant stress. antioxidants: chloride channels: epithelial cells: cystic fibrosis: reactive oxygen species

Asthma is characterized by an increased production of eosinophil-active C-C chemokines by the airway epithelium. Recent studies have identified the presence of important quantities of labile zinc in the conducting airways. We hypothesized that modulation of this labile zinc could influence the production of proinflammatory chemokines in respiratory epithelial cells. The zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and the heavy metal chelator 2,3-dimercapto-l-propanesulfonic acid (DMPS) were used to reduce the labile zinc content of A549, BEAS-2B, and HFL-1 cells. Northern blot analysis and RNase protection assay were used to study the effects of the zinc chelators on mRNA expression. DMPS and TPEN specifically inhibited the production of eotaxin, regulated on activation, normal T-cell expressed, and presumably secreted, and monocyte chemotactic protein-1 in TNF-[alpha]-stimulated respiratory epithelial cells and fibroblasts through labile zinc chelation. The inhibitory effects of DMPS and TPEN were associated with the decreased binding of the zinc-finger transcription factor GATA-1, whereas no change in NF-[kappa]B activation was observed. Together these results demonstrate that modulation of the labile pool of zinc can regulate gene expression and protein synthesis of C-C chemokines in lung epithelial cells and fibroblasts. CC chemokines; inflammation; asthma; regulated on activation, normal T-cell expressed, and presumably secreted; monocyte chemotactic protein

A series of [beta]-lactam derivatives were synthesized and tested to determine the structure-activity relationship for inhibition of human leukocyte elastase (HLE), a serine protease involved in several degenerative lung and tissue diseases. The most potent [IC.sub.50] values were obtained with neutral hydrophobic 7[alpha]-methoxy cephalosporanic acid derivatives. Tryptophanyl-9-fluorenylmethyl ester and N-benzhydryl piperazine derivatives of 7[alpha]-methoxy cephalosporanic acid represent two novel HLE inhibitors, with length of action persisting beyond 24 h. Key words: [beta]-lactams, neutrophil elastase, protease inhibitors, peptides.

PBI-4050 is a novel orally active small-molecule compound with demonstrated anti-fibrotic activity in several models of fibrosis, including lung fibrosis. We present results from our first clinical study of PBI-4050 in patients with idiopathic pulmonary fibrosis (IPF).This 12-week open-label study explored the safety, efficacy and pharmacokinetics of daily oral doses of 800 mg PBI-4050 alone and in combination with nintedanib or pirfenidone in patients with predominantly mild or moderate IPF. Nine patients received PBI-4050 alone, 16 patients received PBI-4050 with nintedanib and 16 patients received PBI-4050 with pirfenidone.PBI-4050 alone or in combination with nintedanib or pirfenidone was well tolerated. Pharmacokinetic profiles for PBI-4050 were similar in the PBI-4050 alone and PBI-4050+nintedanib groups but reduced in the PBI-4050+pirfenidone group, suggesting a drug-drug interaction. There were no significant changes in forced vital capacity (FVC), either in % predicted or mL, from baseline to week 12 for PBI-4050 alone or PBI-4050+nintedanib. In contrast, a statistically significant reduction (p<0.024) in FVC % pred was seen for PBI-4050+pirfenidone after 12 weeks.There were no safety concerns with PBI-4050 alone or in combination with nintedanib or pirfenidone in IPF patients. The stability of FVC between baseline and week 12 looked encouraging for PBI-4050 alone and in combination with nintedanib., Competing Interests: Conflict of interest: N. Khalil has nothing to disclose. Conflict of interest: H. Manganas reports receiving grants from Prometic, during the conduct of the study. Conflict of interest: C.J. Ryerson reports clinical trial participation for Prometic, during the conduct of the study; and receiving grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted work. Conflict of interest: S. Shapera reports receiving: personal fees for speaking engagements from AstraZeneca; grants and personal fees for participation in clinical trials as site PI, membership of advisory boards, grants for knowledge translation research, and honoraria for speaking engagements from Boehringer Ingelheim Canada; grants and personal fees for participation in clinical trials as site PI, membership of advisory boards, grants for clinical epidemiology research, and honoraria for speaking engagements from Hoffman-La Roche Canada, outside the submitted work. S. Shapera participated in clinical trials as site PI for Medimmune, Prometic Canada and Sanofi-Aventis, outside the submitted work. Conflict of interest: A.M. Cantin reports receiving grants and fees for consulting from Prometic, during the conduct of the study. Conflict of interest: P. Hernandez reports receiving: grants paid to his institution for conduct of research from Prometic, during the conduct of the study; personal fees for advisory board work from Actelion, personal fees for advisory board work and CME talks from AstraZeneca, grants paid to his institution for conduct of research and personal fees for advisory board work from Boehringer Ingelheim, grants paid to his institution for conduct of research from CSL Behring, Grifols and Cyclomedica, personal fees for advisory board work from GSK Novartis, Teva and Trudell, and grants and personal fees for advisory board work and CME talks from Bayer, outside the submitted work. Conflict of interest: E.E. Turcotte has nothing to disclose. Conflict of interest: J.M. Parker was employed by Prometic Life Sciences Inc., during the conduct of the study. Conflict of interest: J.E. Moran reports receiving personal fees, cash and equity considerations as an employee and shareholder of Prometic Life Sciences Inc., outside the submitted work. Conflict of interest: G.R. Albert is an employee of Prometic Life Sciences Inc. Conflict of interest: R. Sawtell was employed by Prometic Life Sciences Inc., during the conduct of the study. Conflict of interest: A. Hagerimana was employed by Prometic Life Sciences Inc., during the conduct of the study. Conflict of interest: P. Laurin reports receiving personal fees, cash and equity considerations as an employee and shareholder of Prometic Life Sciences Inc., outside the submitted work; and in addition, has a patent EP 2427417 issued, a patent EP 2427416 issued and a patent EP 2970088 pending. Conflict of interest: L. Gagnon reports receiving personal fees, cash and equity considerations as employee and shareholder of Prometic Life Sciences Inc., outside the submitted work; and has a patent EP 2427417 issued, a patent EP 2427416 issued and a patent EP 2970088 pending. Conflict of interest: F. Cesari reports receiving personal fees, cash and equity considerations as an employee and shareholder of Prometic Life Sciences Inc., outside the submitted work. Conflict of interest: M. Kolb reports receiving: grants from Prometic, during the conduct of the study; grants and personal fees from Roche, Boehringer Ingelheim and GSK, personal fees from Gilead and Genoa, and grants from Actelion, Respivert, Alkermes and Pharmaxis, outside the submitted work., (Copyright ©ERS 2019.)