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

BACKGROUND: Inhalation 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). METHODS: Following 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. RESULTS: The 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. CONCLUSIONS: In 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

A re-evaluation of Holocene relative sea-level change along the Fujian coast, southeastern China

The southeastern China coast is a region of special interest in the study of past and present relative sea-level change, given its distal location from giant ice sheets (far-field regions). During the past decades, a large number of biological, geological, and archaeological sea-level indicators have been retrieved from the Fujian coastal region which allows for recalibration and recalculation of sea-level index points (SLIPs). This study constructs a database of Holocene relative sea-level (RSL) observations for the Fujian coast, southeastern China. The database contains 59 quality-controlled SLIPs which show that RSL for the Fujian coast did not exceed present (0 m) during the Holocene, except potentially during 7.5–5.5 cal. kyr BP and 1.8–0.7 cal. kyr BP. Rates of RSL change were highest during the early Holocene and have decreased over time, due to the diminishing response of the Earth's mantle to glacial isostatic adjustment (GIA) and reduction of meltwater input. A series of sea-level oscillations were recorded in our SLIPs-based reconstructions which might correspond to global climate warming or cooling events. We assessed the spatial variability of RSL histories and compared these with the ICE-6G_C and ANU-ICE GIA model predictions. Substantial misfits between GIA predictions and regional RSL reconstructions were recognized: (1) the deceleration of the early-Holocene sea-level rise ended about one millennia earlier in the ICE-6G_C model than in the SLIPs-based reconstructions; (2) GIA model predictions show a mid-Holocene sea-level highstand of 1–3 m which is absent from our SLIPs-based reconstructions; and (3) all GIA model predicted a gradual RSL fall to 0 m since the middle Holocene, while our reconstruction displays significant RSL oscillations. It is presently unknown whether these misfits are caused by uncertainties in regional tectonic movement estimation or parameters used in the GIA models. Future applications of spatiotemporal statistical techniques are required to better quantify the gradient of the isostatic contribution and to provide improved context for the assessment of the ongoing acceleration of sea-level rise.Ministry of Education (MOE)National Research Foundation (NRF)Submitted/Accepted versionThis work was financially supported by the National Natural Science Foundation of China (Grant No. 42076207 to Fengling Yu); the Funda- mental Research Funds for the Central Universities of Xiamen University (Grant No. 20720190096 to Fengling Yu); the China Postdoctoral Sci- ence Foundation (Grant No. 2021M691862 to Nannan Li); the Singapore Ministry of Education Academic Research Fund MOE2019-T3-1-004 and MOE-T2EP50120-0007, the National Research Foundation Singapore, and the Singapore Ministry of Education, under the Research Centers of Excellence initiative (to Tanghua Li)

Cyclic PaO2 oscillations assessed in the renal microcirculation: correlation with tidal volume in a porcine model of lung lavage

Abstract Background Oscillations of the arterial partial pressure of oxygen induced by varying shunt fractions occur during cyclic alveolar recruitment within the injured lung. Recently, these were proposed as a pathomechanism that may be relevant for remote organ injury following acute respiratory distress syndrome. This study examines the transmission of oxygen oscillations to the renal tissue and their tidal volume dependency. Methods Lung injury was induced by repetitive bronchoalveolar lavage in eight anaesthetized pigs. Cyclic alveolar recruitment was provoked by high tidal volume ventilation. Oscillations of the arterial partial pressure of oxygen were measured in real-time in the macrocirculation by multi-frequency phase fluorimetry and in the renal microcirculation by combined white-light spectrometry and laser-Doppler flowmetry during tidal volume down-titration. Results Significant respiratory-dependent oxygen oscillations were detected in the macrocirculation and transmitted to the renal microcirculation in a substantial extent. The amplitudes of these oscillations significantly correlate to the applied tidal volume and are minimized during down-titration. Conclusions In a porcine model oscillations of the arterial partial pressure of oxygen are induced by cyclic alveolar recruitment and transmitted to the renal microcirculation in a tidal volume-dependent fashion. They might play a role in organ crosstalk and remote organ damage following lung injury

Endexpiratory lung volume measurement correlates with the ventilation/perfusion mismatch in lung injured pigs

Abstract Background In acute respiratory respiratory distress syndrome (ARDS) a sustained mismatch of alveolar ventilation and perfusion (VA/Q) impairs the pulmonary gas exchange. Measurement of endexpiratory lung volume (EELV) by multiple breath-nitrogen washout/washin is a non-invasive, bedside technology to assess pulmonary function in mechanically ventilated patients. The present study examines the association between EELV changes and VA/Q distribution and the possibility to predict VA/Q normalization by means of EELV in a porcine model. Methods After approval of the state and institutional animal care committee 12 anesthetized pigs were randomized to ARDS either by bronchoalveolar lavage (n = 6) or oleic acid injection (n = 6). EELV, VA/Q ratios by multiple inert gas elimination and ventilation distribution by electrical impedance tomography were assessed at healthy state and at five different positive endexpiratory pressure (PEEP) steps in ARDS (0, 20, 15, 10, 5 cmH2O; each maintained for 30 min). Results VA/Q, EELV and tidal volume distribution all displayed the PEEP-induced recruitment in ARDS. We found a close correlation between VA/Q < 0.1 (representing shunt and low VA/Q units) and changes in EELV (spearman correlation coefficient −0.79). Logistic regression reveals the potential to predict VA/Q normalization (VA/Q < 0.1 less than 5%) from changes in EELV with an area under the curve of 0.89 with a 95%-CI of 0.81–0.96 in the receiver operating characteristic. Different lung injury models and recruitment characteristics did not influence these findings. Conclusion In a porcine ARDS model EELV measurement depicts PEEP-induced lung recruitment and is strongly associated with normalization of the VA/Q distribution in a model-independent fashion. Determination of EELV could be an intriguing addition in the context of lung protection strategies

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

BACKGROUND: The lectin-like domain of TNF-alpha can be mimicked by synthetic TIP peptides and represents an innovative pharmacologic option to treat edematous respiratory failure. TIP inhalation was shown to reduce pulmonary edema and improve gas exchange. In addition to its edema resolution effect, TIP peptides may exert some anti-inflammatory properties. The present study therefore investigates the influence of the inhaled TIP peptide AP318 on intrapulmonary inflammatory response in a porcine model of systemic sepsis. METHODS: In a randomized-blinded setting lung injury was induced in 18 pigs by lipopolysaccharide-infusion and a second hit with a short period of ventilator-induced lung stress, followed by a six-hour observation period. The animals received either two inhalations with the peptide (AP318, 2x1 mg kg(-1)) or vehicle. Post-mortem pulmonary expression of inflammatory and mechanotransduction markers were determined by real-time polymerase chain reaction (IL-1beta, IL-6, TNF-alpha, COX-2, iNOS, amphiregulin, and tenascin-c). Furthermore, regional histopathological lung injury, edema formation and systemic inflammation were quantified. RESULTS: Despite similar systemic response to lipopolysaccharide infusion in both groups, pulmonary inflammation (IL-6, TNF-alpha, COX-2, tenascin-c) was significantly mitigated by AP318. Furthermore, a Western blot analysis shows a significantly lower of COX-2 protein level. The present sepsis model caused minor lung edema formation and moderate gas exchange impairment. Six hours after onset pathologic scoring showed no improvement, while gas exchange parameters and pulmonary edema formation were similar in the two groups. CONCLUSION: In summary, AP318 significantly attenuated intrapulmonary inflammatory response even without the presence or resolution of severe pulmonary edema in a porcine model of systemic sepsis-associated lung injury. These findings suggest an anti-inflammatory mechanism of the lectin-like domain beyond mere edema reabsorption in endotoxemic lung injury in vivo