A FIM Study to Assess Safety and Exposure of Inhaled Single Doses of AP301—A Specific ENaC Channel Activator for the Treatment of Acute Lung Injury

Schwameis, Richard; Eder, Sandra; Pietschmann, Helmut; Fischer, Bernhard; Mascher, Hermann; Tzotzos, Susan; Fischer, Hendrik; Lucas, Rudolf; Zeitlinger, Markus; Hermann, Robert Michael

doi:10.1002/jcph.203

Cited by 23 publications

(27 citation statements)

References 25 publications

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“…The lung is vulnerable to damage and a role in SIRS (3). ALI commonly leads to severe hypoxemia, thereby leading to the dysfunction of other organs and potentially multiple organ failure (4). Therefore, ALI is the initial stage in the whole pathological process of SIRS, which results in organ dysfunction and subsequent multiple organ failure.…”

Section: Introductionmentioning

confidence: 99%

Allicin attenuates lipopolysaccharide‑induced acute lung injury in neonatal rats via the PI3K/Akt pathway

et al. 2018

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Allicin is an oxygenated carotenoid derivative that exhibits strong antioxidant activity, which effectively removes reactive oxygen species from the body and has important roles in disease prevention and treatment. Therefore, the present study aimed to investigate whether allicin attenuates lipopolysaccharide (LPS)‑induced acute lung injury (ALI) in neonatal rats and the potential underlying mechanisms. An LPS‑induced ALI neonatal rat model was utilized to assess the therapeutic value and mechanisms of allicin. Following allicin treatment, increases in lung wet/dry ratio and the lung protein concentration were significantly suppressed in LPS‑induced ALI neonatal rats. Furthermore, ELISA results demonstrated that allicin significantly reduced the levels of malondialdehyde, tumor necrosis factor‑α and interleukin‑6, and increased superoxide dismutase activity, in the bronchoalveolar lavage fluid of LPS‑treated rats. Additionally, allicin administration increased the protein expression of Bcl‑2 and reduced the activity of caspase‑3/-9, as determined by western blotting or ELISA, respectively, and increased phosphatidylinositol 3‑kinase (PI3K) and phosphorylated‑Akt protein levels, in LPS‑treated ALI neonatal rats. The results of the present study indicate that allicin attenuate LPS‑induced ALI in neonatal rats by ameliorating oxidative stress, inflammation and apoptosis via the PI3K/Akt pathway. Allicin may be used for development of a novel drug for treatment of ALI.

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Section: Introductionmentioning

confidence: 99%

Allicin attenuates lipopolysaccharide‑induced acute lung injury in neonatal rats via the PI3K/Akt pathway

et al. 2018

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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.…”

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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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“…The TIP peptide has been shown to activate ALC in several animal models of hydrostatic and permeability edema (21,(29)(30)(31). In a recently performed, placebocontrolled, double-blind Phase I clinical trial, TIP peptide (also named AP301) was observed not to induce serious adverse effects upon inhalation (32) Bacterial and viral toxins have been shown to induce significant changes in ENaC P o and/or expression, leading to impaired ALC (33)(34)(35)(36). It is therefore of high clinical relevance to identify novel mechanisms that increase ENaC function during pulmonary edema associated with ARDS and pneumonia, for which no standard therapy exists to date.…”

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confidence: 99%

A Novel Tumor Necrosis Factor–mediated Mechanism of Direct Epithelial Sodium Channel Activation

Czikora

Alli

Bao

et al. 2014

Am J Respir Crit Care Med

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Rationale: Alveolar liquid clearance is regulated by Na 1 uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na 1 -K 1 -ATPase in type II alveolar epithelial cells. Dysfunction of these Na 1 transporters during pulmonary inflammation can contribute to pulmonary edema.Objectives: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na 1 uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY).Methods: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na 1 uptake stimulatory activity.Measurements and Main Results: TIP peptide directly activates ENaC, but not the Na 1 -K 1 -ATPase, upon binding to the carboxyterminal domain of the a subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-a protein expression, by means of blunting the protein kinase C-a pathway. Triple-mutant TNF knock-in mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-a subunit expression.Conclusions: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

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A FIM Study to Assess Safety and Exposure of Inhaled Single Doses of AP301—A Specific ENaC Channel Activator for the Treatment of Acute Lung Injury

Cited by 23 publications

References 25 publications

Allicin attenuates lipopolysaccharide‑induced acute lung injury in neonatal rats via the PI3K/Akt pathway

Allicin attenuates lipopolysaccharide‑induced acute lung injury in neonatal rats via the PI3K/Akt pathway

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

A Novel Tumor Necrosis Factor–mediated Mechanism of Direct Epithelial Sodium Channel Activation

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