TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants

Abstract

BackgroundInhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B).MethodsFollowing animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring.ResultsThe repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring.ConclusionsIn comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

Paradoxical Use of Tumor Necrosis Factor in Treating Pulmonary Edema

“…However, there is accumulating evidence, especially in China, that almost half of patients with CRSwNP in Asian countries have a noneosinophilic pattern of inflammation in their polyp tissue that is characterized by a mixed type 1 and/or type 3 response (5,6). Although the mechanisms that drive these phenotypes are unclear, it has been suggested that differences in Th cell subsets found in polyps from eosinophilic and noneosinophilic patients may play an important role (7). Dendritic cells (DCs) are known to be important in skewing Th responses in the mucosa (8), and thus may be important for skewing Th cells in polyps.…”

“…Importantly, this effect has been mimicked by a small 17-amino acid circular peptide known as TNF inhibitory peptide (TIP; also named AP301). A recent European study compared placebo treatment with TIP inhalation in patients with ALI/ARDS and found that TIP elicited earlier and more pronounced clearance of pulmonary edema (7,8). The molecular mechanism underlying TIP-induced ENaC activation remained uncertain until the study by Czikora and colleagues, published in the September 1, 2014, issue of the Journal (9).…”

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

“…Apart from activating AFC, AP301 also strengthens capillary barrier function in human lung MVEC as well as in rodent models of pneumonia [ 20 ]. In a variety of animal models of ARDS, pulmonary administration of AP301 substantially alleviated pulmonary edema [ 16 – 22 , 39 ]. The present study demonstrated for the first time that AP301 inhalation may reduce EVLWI in severely ill patients with ARDS (SOFA scores ≥11), while the causality of this finding needs further investigation.…”

“…The TIP domain does not activate TNF receptors [ 16 , 17 ] and, in various animal models of lung injury, TIP peptide activated AFC [ 17 – 20 ]. Furthermore, inhaled TIP peptide reduced the extravascular lung water index (EVLWI) in acute lung injury in pigs [ 21 , 22 ]. ENaC activity depends on the product of the surface expression N and the open probability Po .…”

Inhalation therapy with the synthetic TIP-like peptide AP318 attenuates pulmonary inflammation in a porcine sepsis model

“…These findings have not been confirmed in vivo under conditions of systemic sepsis or severe inflammatory response. Based on previous in vitro data the synthetic peptide AP318 may represent a more potent variant of the initially synthesized TIP peptide [ 13 , 14 ], but only showed comparable effects to the first TIP peptide AP301 in a porcine model in vivo [ 15 ]. To further characterize the effects of the lectin-like domain on intrapulmonary inflammation, a porcine model of lipopolysaccharide (LPS)-induced sepsis with an additional ventilator-induced lung injury (VILI) component was examined.…”