RGD Reference Report - Extracellular ATP is a Danger Signal Activating P2X7 Receptor in Lung Inflammation and Fibrosis. - Rat Genome Database

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Extracellular ATP is a Danger Signal Activating P2X7 Receptor in Lung Inflammation and Fibrosis.

Authors: Riteau, N  Gasse, P  Fauconnier, L  Gombault, A  Couegnat, M  Fick, L  Kanellopoulos, J  Quesniaux, VF  Marchand-Adam, S  Crestani, B  Ryffel, B  Couillin, I 
Citation: Riteau N, etal., Am J Respir Crit Care Med. 2010 Jun 3.
RGD ID: 4142535
Pubmed: PMID:20522787   (View Abstract at PubMed)
DOI: DOI:10.1164/rccm.201003-0359OC   (Journal Full-text)

RATIONALE: Pulmonary fibrosis is a devastating as yet untreatable disease. We previously investigated the endogenous mediators released upon lung injury and showed uric acid is a danger signal activating NLRP3 inflammasome in lung inflammation and fibrosis (1). OBJECTIVES: Here we address the role of extracellular adenosine tri-phosphate (eATP) in pulmonary inflammation and fibrosis. METHODS: ATP was quantified in bronchoalveolar lavage fluid (BALF) of controls and patients with idiopathic pulmonary fibrosis. The contribution of eATP as a danger signal was assessed in a murine model of lung fibrosis induced by airway administered bleomycin, an intercalating agent which causes DNA strand breaks. MEASUREMENTS AND MAIN RESULTS: Fibrotic patients have elevated ATP content in BALF in comparison to control individuals. In mice, we report early increase of eATP levels in BALF upon bleomycin administration. Modulation of eATP levels with the ATP-degrading enzyme apyrase greatly reduced BLM-induced inflammatory cell recruitment, lung IL-1beta and TIMP-1 productions, while administration of ATP-gammaS, a stable ATP derivative, enhanced inflammation. P2X7 receptor deficient mice presented a dramatically reduced lung inflammation, with reduced fibrosis markers such as lung collagen content and matrix remodeling proteins TIMP-1 and MMP-9. The acute inflammation depends on a functional pannexin-1 hemichannel protein. In vitro, ATP is released by pulmonary epithelial cells upon BLM-induced stress and this is partly dependent on the presence of functional P2X7 receptor and pannexin-1 hemichannel. CONCLUSION: ATP released from BLM-injured lung cells constitutes a major endogenous danger signal which engages the P2X7 receptor/pannexin-1 axis leading to IL-1beta maturation and lung fibrosis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary fibrosis  ISOIl1b (Mus musculus)4142535; 4142535protein:increased expression:lungRGD 
pulmonary fibrosis  IEP 4142535protein:increased expression:lungRGD 

Objects Annotated

Genes (Rattus norvegicus)
Il1b  (interleukin 1 beta)

Genes (Mus musculus)
Il1b  (interleukin 1 beta)

Genes (Homo sapiens)
IL1B  (interleukin 1 beta)


Additional Information