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Toxicological implication of prostaglandin transporter SLCO2A1 inhibition by cigarette smoke in exacerbation of lung inflammation
- Source :
- Toxicology and applied pharmacology. 405
- Publication Year :
- 2020
-
Abstract
- We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(-/-)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in the lungs of BLM-instilled mice. Bronchoalveolar lavage (BAL) fluid cell analysis indicated more severe inflammation in Slco2a1(-/-) on day 5 after BLM intratracheal instillation, and Slco2a1 deletion increased mRNA expression of pro-inflammatory cytokines (Tnf-α and Il-1β) and chemokine (Ccl5) in BAL cells. Male Slco2a1(-/-) exhibited significantly higher amounts of released Il-1β in BAL fluid, compared with female Slco2a1(-/-), male or female Slco2a1(+/+) group. The amount of PGE2 collected in BAL fluid tended to increase in Slco2a1(-/-) compared with Slco2a1(+/+) group, whereas the PGE2 concentrations in lung tissues were comparable between both groups. Besides, PGE2 accumulated more in BAL fluid of male than that of female mice. Therefore, Slco2a1-deficient male mice were found to be more susceptible to BLM-treatment. Moreover, CS extracts (CSE) significantly reduced initial PGE2 uptake by rat type1 alveolar epithelial cell-like (AT1-L) cells and human SLCO2A1-transfected cells. Exposure of AT1-L cells to CSE resulted in decreased mRNA expression of Slco2a1, suggesting that CS modulates SLCO2A1 function. These results indicate that exacerbated lung inflammation is attributed to an increase in Il-1β peptide and PGE2 accumulation in the alveolar space, which exhibits a male predominance. SLCO2A1 inhibition by CSE is considered to be a new rationale for the lung toxicity of CS.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Pulmonary Fibrosis
Prostaglandin
Gene Expression
Organic Anion Transporters
Inflammation
Toxicology
Bleomycin
CCL5
Dinoprostone
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Internal medicine
Pulmonary fibrosis
medicine
Animals
Humans
Respiratory system
Lung
Pharmacology
Mice, Knockout
medicine.diagnostic_test
Chemistry
Smoking
Tobacco Products
respiratory system
medicine.disease
Disease Models, Animal
030104 developmental biology
Bronchoalveolar lavage
Endocrinology
medicine.anatomical_structure
HEK293 Cells
030220 oncology & carcinogenesis
Cytokines
Female
Tobacco Smoke Pollution
medicine.symptom
Bronchoalveolar Lavage Fluid
Subjects
Details
- ISSN :
- 10960333
- Volume :
- 405
- Database :
- OpenAIRE
- Journal :
- Toxicology and applied pharmacology
- Accession number :
- edsair.doi.dedup.....4b5bd3162e02e69f320a322fe56d88e4