Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF.

Ebener, Simone; Barnowski, Sandra; Wotzkow Alvarez, Carlos; Marti, Thomas; Lopez-Rodriguez, Elena; Crestani, Bruno; Blank, Fabian; Schmid, Ralph; Geiser, Thomas; Funke, Manuela (2017). Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF. American journal of physiology - lung cellular and molecular physiology, 312(1), L42-L55. American Physiological Society 10.1152/ajplung.00119.2016

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Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a median survival of 3 yr. IPF deteriorates upon viral or bacterial lung infection although pulmonary infection (pneumonia) in healthy lungs rarely induces fibrosis. Bacterial lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4), initiating proinflammatory pathways. As TLR4 has already been linked to hepatic fibrosis and scleroderma, we now investigated the role of TLR4 in IPF fibroblasts. Lung tissue sections from patients with IPF were analyzed for TLR4 expression. Isolated normal human lung fibroblasts (NL-FB) and IPF fibroblasts (IPF-FB) were exposed to LPS and transforming growth factor-β (TGF-β) before expression analysis of receptors, profibrotic mediators, and cytokines. TLR4 is expressed in fibroblast foci of IPF lungs as well as in primary NL-FB and IPF-FB. As a model for a gram-negative pneumonia in the nonfibrotic lung, NL-FB and IPF-FB were coexposed to LPS and TGF-β. Whereas NL-FB produced significantly less connective tissue growth factor upon costimulation compared with TGF-β stimulation alone, IPF-FB showed significantly increased profibrotic markers compared with control fibroblasts after costimulation. Although levels of antifibrotic prostaglandin E2 were elevated after costimulation, they were not responsible for this effect. However, significant downregulation of TGF-β receptor type 1 in control fibroblasts seems to contribute to the reduced profibrotic response in our in vitro model. Normal and IPF fibroblasts thus differ in their profibrotic response upon LPS-induced TLR4 stimulation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Pneumologie (Erwachsene)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Live Cell Imaging (LCI)
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Pneumology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Ebener, Simone; Barnowski, Sandra; Wotzkow Alvarez, Carlos; Marti, Thomas; Blank, Fabian; Schmid, Ralph; Geiser, Thomas and Funke, Manuela

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1040-0605

Publisher:

American Physiological Society

Language:

English

Submitter:

Rahel Holderegger

Date Deposited:

16 Jan 2017 08:39

Last Modified:

06 Feb 2018 11:03

Publisher DOI:

10.1152/ajplung.00119.2016

PubMed ID:

27815256

Uncontrolled Keywords:

Toll-like receptor 4; connective tissue growth factor; fibroblasts; idiopathic pulmonary fibrosis; lipopolysaccharide

BORIS DOI:

10.7892/boris.93076

URI:

https://boris.unibe.ch/id/eprint/93076

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