Evidence map›Paper›PMID 41316271›Full record

ArticleRespiratory research2025

C6 peptide blockade of Hv1 channels inhibits neutrophil migration into the lungs to suppress Pseudomonas aeruginosa-induced acute lung injury.

Ruiming Zhao, Benjamin Lopez, Nairrita Majumder, Aren Kasparian, Punyanuch Hua, Hui Dai, Maha Nayak, Tatiana Zyrianova, Clove Taylor, Yiwen Ding and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Respiratory research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Ruiming ZhaoDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA.
Benjamin LopezDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Nairrita MajumderDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Aren KasparianDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Punyanuch HuaDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA.
Hui DaiDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA.
Maha NayakDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA.
Tatiana ZyrianovaDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Clove TaylorDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Yiwen DingDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA.
Colin J SalleeDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Anil SapruDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Steve A N GoldsteinDepartments of Pediatrics and Physiology & Biophysics, School of Medicine, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA, 92697, USA. sgoldst2@uci.edu.
Andreas SchwingshacklDepartment of Pediatrics, University of California Los Angeles, Los Angeles, CA, 90095, USA. aschwingshackl@mednet.ucla.edu.

Funding

hHv1 channels in neutrophils and the innate immune inflammatory responseR01HL159711 · NHLBI · UNIVERSITY OF CALIFORNIA-IRVINE · PI GOLDSTEIN, STEVE A N, ZHAO, RUIMING · 2022 to 2025
$2.4M
Identification of botanical hHv1 channel blockers as analgesics for neuropathic painR33AT012544 · NCCIH · UNIVERSITY OF CALIFORNIA-IRVINE · PI GOLDSTEIN, STEVE A N, WU, LONG-JUN · 2024 to 2025
$873k
American Heart Association 20TPA35490010American Heart Association 23CDA1052265American Lung Association IA-678511NCCIH NIH HHS AT012544NCCIH NIH HHS R33 AT012544NHLBI NIH HHS HL146821NHLBI NIH HHS HL159711NHLBI NIH HHS R01 HL159711U.S. Department of Defense W81XWH2210040
6 · The paper itself

Abstract

backgroundAcute Lung Injury (ALI) and its most severe form, Acute Respiratory Distress Syndrome (ARDS), are critical pulmonary conditions characterized by life-threatening acute hypoxic respiratory failure, affecting over three million individuals globally each year. ALI involves alveolar inflammation and disruption of the alveolar-capillary barrier, primarily driven by neutrophil infiltration and the release of inflammatory mediators. In our previous study using a lipopolysaccharide (LPS)-induced mouse model of ALI, we demonstrated that C6, a peptide inhibitor of voltage-gated proton channels (Hv1), ameliorates lung injury, identifying Hv1 as a potential therapeutic target. However, (i) whether the anti-inflammatory effects of C6 are translatable to a clinically relevant live bacterial infection model, and (ii) the molecular mechanisms underlying these anti-inflammatory effects, remain unknown, and are a crucial next step towards targeted rational drug development.

methodsTo induce ALI, we used an intratracheal Pseudomonas aeruginosa infection model, a gram-negative bacterium relevant in ventilated and immunocompromised patients. A separate group of infected mice also received intravenous treatment with C6 (4 mg/kg). Lung injury severity was evaluated using histopathological analysis. Bronchoalveolar lavage (BAL) fluid was collected to quantify neutrophil infiltration and proinflammatory cytokines concentrations. In addition, reactive oxygen species (ROS) production and intracellular calcium levels in BAL neutrophils were measured. RNA sequencing of BAL neutrophils was conducted to assess C6-induced transcriptional changes. Key findings were validated in vitro using human neutrophils.

resultsC6 mitigates P. aeruginosa-induced ALI in mice by reducing neutrophil infiltration into the alveolar space by ~ 86%, improving lung injury scores, decreasing BAL fluid proinflammatory cytokine levels, and suppressing neutrophil ROS production and intracellular calcium levels. RNA sequencing of BAL neutrophils revealed 51 downregulated genes, including key regulators of neutrophil migration, cytokine release, and ROS production; only three genes were upregulated and they also have roles in neutrophil immune defense. In human neutrophils, C6 similarly inhibited chemotaxis and reduced ROS and cytokine release, and calcium influx.

conclusionsTargeting Hv1 with C6 effectively protects against P. aeruginosa-induced ALI by limiting neutrophil recruitment and activation. These findings establish C6 as a promising therapeutic candidate against infectious ALI and provide important mechanistic insights into its immunomodulatory effects on neutrophils.

Indexed as

Acute Lung InjuryIon ChannelsLungNeutrophil InfiltrationNeutrophilsPseudomonas aeruginosaPseudomonas InfectionsAnimalsHumansMaleMiceMice, Inbred C57BLHv1 proton channel, mouseIon ChannelsAcute lung injury (ALI)NeutrophilsRNA sequencing (RNA-seq)Voltage-gated proton channels.

Identifiers

PMID41316271
PMCPMC12661846

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.