Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge

Mole, Sarah; Harry, Anya; Fowler, Andrew; Hotee, Sarah; Warburton, J; Waite, Sarah; Beerahee, Misba; Behm, David J.; Badorrek, Philipp; Müller, Meike; Faulenbach, Cornelia; Lazaar, Aili L.; Hohlfeld, Jens M.

doi:10.1016/j.pupt.2020.101977

Cited by 13 publications

(9 citation statements)

References 33 publications

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“…The consistent detection of the DEspR+ neutrophil-subset across three species in different LPS-induced neutrophilic inflammation models with increasing severity – 1) segmental neutrophilic inflammation and pulmonary-vascular barrier disruption model in human volunteers ( 33 ), 2) transient hypoxemia/ALI in macaques, and 3) high-mortality encephalopathy in rats – independently corroborate the neutrophil-subset with surface immunotype DEspR+CD11b+/CD66b+. These results confirm identity of this subset as detected in patients with ARDS, COVID-19-ARDS ( 23 ), and more recently, in spontaneous intracerebral hemorrhage (sICH) patients ( 34 ).…”

Section: Discussionmentioning

confidence: 66%

“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models

et al. 2022

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Background and objectiveThe correlation (Rs > 0.7) of neutrophils expressing the dual endothelin1/signal peptide receptor (DEspR+CD11b+/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted in vivo studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models.MethodsWe performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species – human, rhesus macaque, rat – with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy in vivo in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats.ResultsChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (P =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (P <0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (P =0.03) and neutrophil influx into BALF (P =0.0001) in LPS-ALI vs vehicle mock-treated LPS-ALI macaques. Ex vivo live cell imaging of macaque neutrophils detected greater “intrinsic adhesion to hard-surface” in DEspR+ vs DEspR[-] neutrophils (P <0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (P <0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (P =0.0007) and exhibited brain target engagement and bioeffects.ConclusionDetection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.

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Section: Discussionmentioning

confidence: 66%

“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models

et al. 2022

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“…However, the urea correction method relies on the assumption that there is no extraction of urea nor of the drug analyte from surrounding lung tissue during the course of the BAL procedure (which takes ~2-3 minutes) and that no urea leaks into the alveolar compartment with disease. In this respect, it has been demonstrated that the BAL urea dilution method is affected in endotoxin-inflamed human lungs (Mole et al, 2020). Second, This article is protected by copyright.…”

Section: Discussionmentioning

confidence: 98%

“…However, the urea correction method relies on the assumption that there is no extraction of urea nor of the drug analyte from surrounding lung tissue during the course of the BAL procedure (which takes $2-3 min) and that no urea leaks into the alveolar compartment with disease. In this context, the BAL urea dilution method is known to be affected in endotoxin-inflamed human lungs (Mole et al, 2020). Second, BAL is not spatially defined, so the sample collected is a mix of ELF from central and peripheral lung from the 4th to 5th generation down to the alveoli (20-23 generation).…”

Section: Discussionmentioning

confidence: 99%

Lung pharmacokinetics of inhaled and systemic drugs: A clinical evaluation

Sadiq

Holz

Ellinghusen

et al. 2021

British J Pharmacology

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United Kingdom) for scientific exchange and technical advice. We thank the clinical study volunteers for their participation and the site staff for their diligent study conduct. We also thank Richard Claes, PhD, of PharmaGenesis London (London, United Kingdom) for providing medical writing support, which was funded by AstraZeneca (Gothenburg, Sweden) in accordance with Good Publication Practice 3 (GPP3) guidelines (http://www.ismpp.org/gpp3).

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“…The safety and tolerability of the pharmacologic inhibitor of TRPV4, GSK, has been demonstrated in both healthy human subjects and in those with compensated heart failure (79). There have been clinical trials evaluating the potential therapeutic benefit of GSK for several conditions including: cardiogenic pulmonary edema, chronic cough, and LPSinduced lung injury, although the trials for lung injury and chronic cough were terminated early because they were unlikely to reach their primary end-points (80)(81)(82). The scientific basis for these trials is to inhibit TRPV4's role in vasodilation and vascular permeability, which is likely mediated by both endothelial and immune cell dysfunction (83).…”

Section: Discussionmentioning

confidence: 99%

Stretching the Function of Innate Immune Cells

et al. 2021

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The importance of innate immune cells to sense and respond to their physical environment is becoming increasingly recognized. Innate immune cells (e.g. macrophages and neutrophils) are able to receive mechanical signals through several mechanisms. In this review, we discuss the role of mechanosensitive ion channels, such as Piezo1 and transient receptor potential vanilloid 4 (TRPV4), and cell adhesion molecules, such as integrins, selectins, and cadherins in biology and human disease. Furthermore, we explain that these mechanical stimuli activate intracellular signaling pathways, such as MAPK (p38, JNK), YAP/TAZ, EDN1, NF-kB, and HIF-1α, to induce protein conformation changes and modulate gene expression to drive cellular function. Understanding the mechanisms by which immune cells interpret mechanosensitive information presents potential targets to treat human disease. Important areas of future study in this area include autoimmune, allergic, infectious, and malignant conditions.

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Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge

Cited by 13 publications

References 33 publications

“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models

“Rogue” neutrophil-subset [DEspR+CD11b+/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury – studies in human, macaque and rat LPS-inflammation models

Lung pharmacokinetics of inhaled and systemic drugs: A clinical evaluation

Stretching the Function of Innate Immune Cells

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