Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial

Krenn, Katharina; Lucas, Rudolf; Croizé, Adrien; Boehme, Stefan; Klein, Klaus Ulrich; Hermann, Robert Michael; Markstaller, Klaus; Ullrich, Robert C.

doi:10.1186/s13054-017-1795-x

Cited by 47 publications

(40 citation statements)

References 46 publications

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“…[22]. Clinical trials have also shown that inhalation of ENaC activator significantly reduces the aextravascular lung water index (EVLWI) in ARDS patients [23]. In this experiment, we observed that the ENaC expression was low in the LPS group, while Dex increased α-, β-and γ-ENaC expression in LPS induced ALI and LPS stimulated A549 cells.…”

Section: Discussionmentioning

confidence: 52%

Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

Jiang¹,

Huang

et al. 2020

Preprint

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Background: Pulmonary edema is a hallmark in acute lung injury(ALI). Researchers have also revealed that dexmedetomidine (Dex) alleviate pulmonary edema following ALI, but the mechanism is unclear.The alveolar epithelial sodium channel (ENaC)-mediated alveolar fluid clearance (AFC) plays an important role in reducing pulmonary edema. In this study, we attempted to investigate the effect of Dex on ENaC in modulating AFC and its mechanism. Methods: LipopolysacchAride (LPS) was used to induce ALI in rat and alveolar epithelial cell injury in A549 cell. The rats were randomly allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002 (n = 6 per group). In vitro, cells (1×10 6 cells/cm 2 ) were subcultured in six-well plates, then cells were allotted into the following groups: control, LPS, LPS+Dex, LPS+Dex+LY294002. Results: In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC.Moreover, Dex prevented LPS-induced downregulation of α-, β- and γ-ENaC expression. In A549 cells stimulated with LPS, Dex attanuated LPS-mediated cell injury and the downregulation of α-, β- and γ-ENaC expression. Howere, all of which was blocked by PI3K inhibitor LY294002,suggesting that the protective role of Dex is PI3K dependent. Additionaly, Dex increases the expression of phosphorylated Akt and reduces the expression of Need4-2 in vivo and vitro, while the LY294002 reverses the effect of Dex, indicating that Dex activates the PI3K/Akt/Nedd4-2 signaling pathway. C onclusio ns: Dex alleviates pulmonary edema by promoting AFC, and the mechanism is partly related to up-regulation of ENaC expression via PI3K/Akt/Nedd4-2 signaling pathway.

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Section: Discussionmentioning

confidence: 52%

Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

Jiang¹,

Huang

et al. 2020

Preprint

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“…25,26 Support for this experimental direction is provided by the finding that inhaled TIP peptide (a.k.a. AP301 and solnatide) was recently found to be safe in a phase 1 clinical trial in volunteers 27 and displayed promising activities on lung function in 2 phase 2a clinical trials in patients with acute lung injury 28 and after lung transplantation. 29 Initially, we assessed whether TIP peptide treatment could blunt pathology and restore renal function during the course of acute nephritis in a murine NTN model and whether this was primarily mediated by renal or systemic activities of the TIP peptide.…”

mentioning

confidence: 99%

The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

Madaio

Czikora

Kvirkvelia

et al. 2019

Kidney International

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In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's a subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation.Kidney International (2019) 95, 1359-1372; https://doi.

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“…There was no significant improvement in lung liquid clearance over all patients, as assessed by the PiCCO method. However, there was a significant increase in extravascular lung water removal in those patients with a sequential organ failure assessment score higher than or equal to 11, representing more than 50% of the subjects in this trial ( 358 ). One hypothesis for this observation is that patients in this group, apart from suffering from impaired AFC capacity, might also suffer from more severe capillary barrier dysfunction.…”

Section: Cytokine-ion Channel Interactionmentioning

confidence: 92%

“…For experimental purposes to mimic the TNF lectin-like domain, the amino acid sequence-identic synthetic 17 amino acid peptide which has shown to biologically mimic the lectin-like tip domain of TNF ( 353 – 355 ), as described above, has been used in a variety of experimental researches. It, moreover, gave rise to a therapeutic candidate that was recently evaluated in clinical trials (a.k.a AP301 and Solnatide) ( 356 – 358 ).…”

Section: Cytokine-ion Channel Interactionmentioning

confidence: 99%

Cytokine–Ion Channel Interactions in Pulmonary Inflammation

et al. 2018

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The lungs conceptually represent a sponge that is interposed in series in the bodies’ systemic circulation to take up oxygen and eliminate carbon dioxide. As such, it matches the huge surface areas of the alveolar epithelium to the pulmonary blood capillaries. The lung’s constant exposure to the exterior necessitates a competent immune system, as evidenced by the association of clinical immunodeficiencies with pulmonary infections. From the in utero to the postnatal and adult situation, there is an inherent vital need to manage alveolar fluid reabsorption, be it postnatally, or in case of hydrostatic or permeability edema. Whereas a wealth of literature exists on the physiological basis of fluid and solute reabsorption by ion channels and water pores, only sparse knowledge is available so far on pathological situations, such as in microbial infection, acute lung injury or acute respiratory distress syndrome, and in the pulmonary reimplantation response in transplanted lungs. The aim of this review is to discuss alveolar liquid clearance in a selection of lung injury models, thereby especially focusing on cytokines and mediators that modulate ion channels. Inflammation is characterized by complex and probably time-dependent co-signaling, interactions between the involved cell types, as well as by cell demise and barrier dysfunction, which may not uniquely determine a clinical picture. This review, therefore, aims to give integrative thoughts and wants to foster the unraveling of unmet needs in future research.

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Inhaled AP301 for treatment of pulmonary edema in mechanically ventilated patients with acute respiratory distress syndrome: a phase IIa randomized placebo-controlled trial

Cited by 47 publications

References 46 publications

Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

Dexmedetomidine alleviates pulmonary edema through epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS- induced acute lung injury

The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis

Cytokine–Ion Channel Interactions in Pulmonary Inflammation

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