A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetic Effects of ARO-ENaC in Normal Healthy Volunteers and Safety, Tolerability and Efficacy in Patients With Cystic Fibrosis

The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics (PK) of single doses of ARO-ENaC in healthy adult volunteers; and to evaluate the safety, tolerability, PK and efficacy of multiple doses of ARO-ENaC in patients with pulmonary cystic fibrosis.

开始日期2020-08-10

申办/合作机构

Arrowhead Pharmaceuticals, Inc.

100 项与 αvβ6 x ENaCα 相关的临床结果

登录后查看更多信息

100 项与 αvβ6 x ENaCα 相关的转化医学

登录后查看更多信息

0 项与 αvβ6 x ENaCα 相关的专利（医药）

登录后查看更多信息

项与 αvβ6 x ENaCα 相关的文献（医药）

2005-05-01·Journal of Biological Chemistry2区 · 生物学

Interleukin-1β Decreases Expression of the Epithelial Sodium Channel α-Subunit in Alveolar Epithelial Cells via a p38 MAPK-dependent Signaling Pathway

2区 · 生物学

Article

作者: Sheppard, Dean ; Matthay, Michael A. ; Pittet, Jean-Francois ; Canessa, Cecilia M. ; Pespeni, Melissa ; Kawakatsu, Hisaaki ; Gartland, Brandi ; Roux, Jeremie

Acute lung injury (ALI) is a devastating syndrome characterized by diffuse alveolar damage, elevated airspace levels of pro-inflammatory cytokines, and flooding of the alveolar spaces with protein-rich edema fluid. Interleukin-1beta (IL-1beta) is one of the most biologically active cytokines in the distal airspaces of patients with ALI. IL-1beta has been shown to increase lung epithelial and endothelial permeability. In this study, we hypothesized that IL-1beta would decrease vectorial ion and water transport across the distal lung epithelium. Therefore, we measured the effects of IL-1beta on transepithelial current, resistance, and sodium transport in primary cultures of alveolar epithelial type II (ATII) cells. IL-1beta significantly reduced the amiloride-sensitive fraction of the transepithelial current and sodium transport across rat ATII cell monolayers. Moreover, IL-1beta decreased basal and dexamethasone-induced epithelial sodium channel alpha-subunit (alpha ENaC) mRNA levels and total and cell-surface protein expression. The inhibitory effect of IL-1beta on alpha ENaC expression was mediated by the activation of p38 MAPK in both rat and human ATII cells and was independent of the activation of alpha v beta6 integrin and transforming growth factor-beta. These results indicate that IL-1beta may contribute to alveolar edema in ALI by reducing distal lung epithelial sodium absorption. This reduction in ion and water transport across the lung epithelium is in large part due to a decrease in alpha ENaC expression through p38 MAPK-dependent inhibition of alpha ENaC promoter activity and to an alteration in ENaC trafficking to the apical membrane of ATII cells.