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Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis.

Nakanishi T, Hasegawa Y, Mimura R, Wakayama T, Uetoko Y, Komori H, Akanuma S, Hosoya K, Tamai I - PLoS ONE (2015)

Bottom Line: Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1).Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1.In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

ABSTRACT
Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

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PGE2 levels in lung tissue homogenates and BALF of BLM-treated mice.(A) PGE2 concentrations were quantified in lung tissue homogenates of WT (open column) and Slco2a1-/- (closed column) mice. (B) Amounts of PGE2 in BALF were measured by means of LC-MS/MS as described in Material and Methods or S1 Table. Each column shows the mean of four individual determinants with SEM. Student’s t-test was used for statistical analysis (**, p<0.01).
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pone.0123895.g005: PGE2 levels in lung tissue homogenates and BALF of BLM-treated mice.(A) PGE2 concentrations were quantified in lung tissue homogenates of WT (open column) and Slco2a1-/- (closed column) mice. (B) Amounts of PGE2 in BALF were measured by means of LC-MS/MS as described in Material and Methods or S1 Table. Each column shows the mean of four individual determinants with SEM. Student’s t-test was used for statistical analysis (**, p<0.01).

Mentions: To understand the relationship between PGE2 disposition and worsened fibrosis in Slco2a1-/- mice, the amounts of PGE2 in lung homogenates and BALF were quantified. PGE2 concentration in lung tissue homogenates tended to decrease (Fig 5A, p = 0.24), while the quantity of PGE2 recovered in BALF was greatly increased (Fig 5B, p = 0.008), compared to WT mice. However, there was no difference of PGE2 levels in lung homogenates and BALF between untreated and BLM-treated WT mice (Fig 3A and 3B). Metabolomics analysis showed that there were not any significant differences of other eicosanoids except for PGE2 in BALF between WT and Slco2a1-/- mice (S1 Table).


Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis.

Nakanishi T, Hasegawa Y, Mimura R, Wakayama T, Uetoko Y, Komori H, Akanuma S, Hosoya K, Tamai I - PLoS ONE (2015)

PGE2 levels in lung tissue homogenates and BALF of BLM-treated mice.(A) PGE2 concentrations were quantified in lung tissue homogenates of WT (open column) and Slco2a1-/- (closed column) mice. (B) Amounts of PGE2 in BALF were measured by means of LC-MS/MS as described in Material and Methods or S1 Table. Each column shows the mean of four individual determinants with SEM. Student’s t-test was used for statistical analysis (**, p<0.01).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414486&req=5

pone.0123895.g005: PGE2 levels in lung tissue homogenates and BALF of BLM-treated mice.(A) PGE2 concentrations were quantified in lung tissue homogenates of WT (open column) and Slco2a1-/- (closed column) mice. (B) Amounts of PGE2 in BALF were measured by means of LC-MS/MS as described in Material and Methods or S1 Table. Each column shows the mean of four individual determinants with SEM. Student’s t-test was used for statistical analysis (**, p<0.01).
Mentions: To understand the relationship between PGE2 disposition and worsened fibrosis in Slco2a1-/- mice, the amounts of PGE2 in lung homogenates and BALF were quantified. PGE2 concentration in lung tissue homogenates tended to decrease (Fig 5A, p = 0.24), while the quantity of PGE2 recovered in BALF was greatly increased (Fig 5B, p = 0.008), compared to WT mice. However, there was no difference of PGE2 levels in lung homogenates and BALF between untreated and BLM-treated WT mice (Fig 3A and 3B). Metabolomics analysis showed that there were not any significant differences of other eicosanoids except for PGE2 in BALF between WT and Slco2a1-/- mice (S1 Table).

Bottom Line: Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1).Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1.In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

ABSTRACT
Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

Show MeSH
Related in: MedlinePlus