Evidence map›Paper›PMID 25862813›Full record

ArticleJournal of immunology (Baltimore, Md. : 1950)2015

Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut.

Chhinder P Sodhi, Hongpeng Jia, Yukihiro Yamaguchi, Peng Lu, Misty Good, Charlotte Egan, John Ozolek, Xiaorong Zhu, Timothy R Billiar, David J Hackam

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of immunology (Baltimore, Md. : 1950), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed
7.3field-weighted citation impact, top 2% of its field
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

53 citing papers in PubMed, 77 citations in OpenAlex.

  1. Article
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  7. DPP4 inhibition curbs systemic inflammation.Critical care (London, England) · 2025
    Observational
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  14. Abnormal intestinal milieu in posttraumatic stress disorder is not impacted by treatment that improves symptoms.American journal of physiology. Gastrointestinal and liver physiology · 2022
    Article
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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

10 authors at 5 institutions in 1 country.

Chhinder P SodhiDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
Hongpeng JiaDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
Yukihiro YamaguchiDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
Peng LuDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
Misty GoodDivision of Newborn Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Charlotte EganDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
John OzolekDivision of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Xiaorong ZhuDepartment of Medicine, Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL 60637; and.
Timothy R BilliarDivision of Trauma and General Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213.
David J HackamDivision of General Pediatric Surgery, Department of Surgery, Johns Hopkins University, Baltimore, MD 21287; Dhackam1@jhmi.edu.
Johns Hopkins Medicine · USJohns Hopkins University · USChildren's Hospital of Pittsburgh · USUniversity of Chicago · USUniversity of Pittsburgh · US

Funding

Regulation of Intestinal Mucosal Injury & Repair After Trauma/Hemorrhagic ShockP50GM053789 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BILLIAR, TIMOTHY R · 1997 to 2013
$18.0M
TLR4 Signaling in the Pathogenesis of Surgical Necrotizing EnterocolitisR01GM078238 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HACKAM, DAVID J · 2006 to 2019
$3.9M
Modulation of TLR4 and TLR9 Signaling in NECR01DK083752 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HACKAM, DAVID J · 2008 to 2016
$3.4M
NIDDK NIH HHS R01 DK083752NIDDK NIH HHS R01DK083752NIGMS NIH HHS P50 GM053789NIGMS NIH HHS P50-GM-53789NIGMS NIH HHS R01 GM078238NIGMS NIH HHS R01GM078238
6 · The paper itself

Abstract

The mechanisms that lead to the development of remote lung injury after trauma remain unknown, although a central role for the gut in the induction of lung injury has been postulated. We hypothesized that the development of remote lung injury after trauma/hemorrhagic shock requires activation of TLR4 in the intestinal epithelium, and we sought to determine the mechanisms involved. We show that trauma/hemorrhagic shock caused lung injury in wild-type mice, but not in mice that lack TLR4 in the intestinal epithelium, confirming the importance of intestinal TLR4 activation in the process. Activation of intestinal TLR4 after trauma led to increased endoplasmic reticulum (ER) stress, enterocyte apoptosis, and the release of circulating HMGB1, whereas inhibition of ER stress attenuated apoptosis, reduced circulating HMGB1, and decreased lung injury severity. Neutralization of circulating HMGB1 led to reduced severity of lung injury after trauma, and mice that lack HMGB1 in the intestinal epithelium were protected from the development of lung injury, confirming the importance of the intestine as the source of HMGB1, whose release of HMGB1 induced a rapid protein kinase C ζ-mediated internalization of surface tight junctions in the pulmonary epithelium. Strikingly, the use of a novel small-molecule TLR4 inhibitor reduced intestinal ER stress, decreased circulating HMGB1, and preserved lung architecture after trauma. Thus, intestinal epithelial TLR4 activation leads to HMGB1 release from the gut and the development of lung injury, whereas strategies that block upstream TLR4 signaling may offer pulmonary protective strategies after trauma.

Indexed as

Acute Lung InjuryAnimalsCell LineDisease Models, AnimalHMGB1 ProteinHumansIntestinal MucosaMiceMice, KnockoutReal-Time Polymerase Chain ReactionShock, HemorrhagicToll-Like Receptor 4HMGB1 ProteinHMGB1 protein, mouseTlr4 protein, mouseToll-Like Receptor 4

Identifiers

PMID25862813
PMCPMC4417407
OpenAlexW1922823402

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.