Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

Taiki Kida; Shinya Ayabe; Keisuke Omori; Tatsuro Nakamura; Toko Maehara; Kosuke Aritake; Yoshihiro Urade; Takahisa Murata

doi:10.1371/journal.pone.0167729

Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

PLoS One. 2016 Dec 19;11(12):e0167729. doi: 10.1371/journal.pone.0167729. eCollection 2016.

Authors

Taiki Kida¹, Shinya Ayabe¹, Keisuke Omori¹, Tatsuro Nakamura¹, Toko Maehara¹, Kosuke Aritake², Yoshihiro Urade², Takahisa Murata¹

Affiliations

¹ Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
² International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki, Japan.

Abstract

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

MeSH terms

Animals
Bleomycin / adverse effects*
Chemokine CCL2 / genetics
Collagen / metabolism
Cyclooxygenase 2 / genetics
Disease Models, Animal
Gene Knockout Techniques
Intramolecular Oxidoreductases
Isomerases / genetics*
Lung / metabolism
Lung / pathology
Macrophages / metabolism
Mice
Neutrophil Infiltration / drug effects
Pneumonia / chemically induced*
Pneumonia / genetics
Pneumonia / metabolism
Prostaglandin D2 / metabolism*
Pulmonary Fibrosis / chemically induced*
Pulmonary Fibrosis / genetics
Pulmonary Fibrosis / metabolism
Pulmonary Fibrosis / pathology
Tumor Necrosis Factor-alpha / genetics

Substances

Ccl2 protein, mouse
Chemokine CCL2
Tumor Necrosis Factor-alpha
Bleomycin
Collagen
Ptgs2 protein, mouse
Cyclooxygenase 2
Isomerases
Intramolecular Oxidoreductases
HPGDS protein, mouse
Prostaglandin D2

Grants and funding

Grant-in-Aid for Scientific Research from The Japan Society for the Promotion of Science, 25252049, http://www.jsps.go.jp/english/index.html; Foundation for Dietary Scientific Research, http://www.z-ssk.org/about/outline.html; Cardiovascular Research Fund, http://www.jcvrf.jp/; Kurozumi Medical Foundation, http://www.kmf.or.jp/index.html; Naito Foundation, https://www.naito-f.or.jp/jp/index.php; Suzuken Memorial Foundation, http://suzukenzaidan.or.jp/index.html; Nipponham Foundation, https://www.miraizaidan.or.jp/public/detail01.html; Sapporo Bioscience Foundation, http://www.sapporoholdings.jp/english/index.html; and Japan Foundation for Pediatric Research, http://www.jfpedres.or.jp/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.