Particulate Matter Increases the Severity of Bleomycin-Induced Pulmonary Fibrosis through KC-Mediated Neutrophil Chemotaxis
Open Access
- 28 December 2019
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (1), 227
- https://doi.org/10.3390/ijms21010227
Abstract
Background: Although particular matter (PM) increases incidence and severity of idiopathic pulmonary fibrosis, the underlying mechanism remains elusive. Methods: The effects of PM were evaluated in a murine model of bleomycin-induced pulmonary fibrosis. Mice were divided into four groups, receiving: (1) Saline (control), (2) bleomycin, (3) PM, or (4) bleomycin plus PM (Bleo+PM). Additional groups of Bleo+PM mice were treated with sivelestat (an inhibitor of neutrophil elastase) or reparixin (a C-X-C motif chemokine receptor 2 antagonist), or were genetically modified with keratinocyte chemoattractant (KC) deletion. Results: Pulmonary fibrosis was not observed in the control or PM groups. Bleomycin induced pulmonary fibrosis within 14 days. The Bleo+PM group showed worse pulmonary fibrosis when compared to the bleomycin group. Analyses of immune cell profile and chemokine/cytokine concentrations at day 2-bronchoalveolar lavage fluid (BALF) revealed that the Bleo+PM group had increased neutrophil number and elastase level and KC concentration compared to the bleomycin group. Neutrophil elastase activated the Smad2/Smad3/α-SMA pathway to induce collagen deposition, while sivelestat abrogated the increased severity of pulmonary fibrosis caused by PM. Chemotaxis assay revealed that BALF of the Bleo+PM group recruited neutrophil, which was dependent on KC. Further, genetic KC deletion or pharmaceutical inhibition of KC binding to CXCR2 with reparixin ameliorated the PM-induced increased severity of pulmonary fibrosis. Conclusions: These data provide evidence that the PM-induced increased severity of pulmonary fibrosis depends on KC-mediated neutrophil chemotaxis and give additional mechanic insight that will aid in the development of therapeutic strategies.Funding Information
- Ministry of Science and Technology (MOST 106-2314-B-075-030-MY3)
This publication has 36 references indexed in Scilit:
- Clinical Course and Prediction of Survival in Idiopathic Pulmonary FibrosisAmerican Journal of Respiratory and Critical Care Medicine, 2011
- The murine IL-8 homologues KC, MIP-2, and LIX are found in endothelial cytoplasmic granules but not in Weibel-Palade bodiesJournal of Leukocyte Biology, 2009
- Chemokine CXCL1/KC and its Receptor CXCR2 Are Responsible for Neutrophil Chemotaxis in Adenoviral KeratitisJournal of Interferon & Cytokine Research, 2009
- Role of the Chemokine Receptor CXCR2 in Bleomycin-Induced Pulmonary Inflammation and FibrosisAmerican Journal of Respiratory Cell and Molecular Biology, 2009
- The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?The International Journal of Biochemistry & Cell Biology, 2008
- Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in miceBritish Journal of Pharmacology, 2008
- The chemokine receptors CXCR1/CXCR2 modulate antigen‐induced arthritis by regulating adhesion of neutrophils to the synovial microvasculatureArthritis & Rheumatism, 2008
- Mice Lacking Neutrophil Elastase Are Resistant to Bleomycin-Induced Pulmonary FibrosisThe American Journal of Pathology, 2007
- Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis.American Journal of Respiratory and Critical Care Medicine, 1997
- Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitisThe Lancet, 1996