ACTIVATION OF SOMATOSTATIN RECEPTORS ATTENUATES PULMONARY FIBROSIS

raphael borie ¹, aurélie fabre ¹, fabienne prost ¹, joelle marchal-sommé ¹, rachida lebtahi ², sylvain marchand-adam ³, michel aubier ³, paul soler ⁴ and bruno crestani ^3*

¹ INSERM U700, France
² Service de médecine nucléaire, hôpital Bichat, France
³ INSERM U 700 and Service de Pneumologie A, Hôpital Bichat, France
⁴ INSERM U 700, France

^* To whom correspondence should be addressed. E-mail: bruno.crestani{at}bch.aphp.fr.

Accepted 27 July 2007

Abstract

Somatostatin analogs may have antifibrotic properties in the lung. The aim of this study was to evaluate the expression of the five somatostatin receptors sst1 to sst5 in the normal and fibrotic mouse lung and the action of SOM230 (pasireotide), a new somatostatin analog with a long half life, in bleomycin-induced lung fibrosis and in human lung fibroblasts in vitro. After intratracheal injection of bleomycin, C57Bl6 male mice received one daily sub-cutaneous injection of SOM230 or saline. The lungs were evaluated on day 3, 7 and 14 after bleomycin. We found that all the somatostatin receptors were expressed in the normal mouse lung. Sst2 receptor mRNA expression was increased after bleomycin. SOM230 improved mice survival (69% vs 44%, P=0.024) and reduced lung collagen content at day 14, and decreased lung collagen-1 mRNA at day 7. SOM230 reduced the BAL inflammatory cells influx at day 3, decreased lung CTGF mRNA and TGF- mRNA, and increased lung hepatocyte growth factor and keratinocyte growth factor mRNA. The sst2 receptor was strongly expressed in the human lung, either normal or fibrotic, particularly by fibroblasts. In vitro, SOM230 reduced BrdU incorporation by control human lung fibroblasts cultured in basal conditions or with TGF-, and reduced alpha-1 collagen-1 mRNA expression in TGF- stimulated fibroblasts. We conclude that SOM230 attenuates bleomycin-induced pulmonary fibrosis in mice and human lung fibroblasts activation. This study points to a potential new approach for treating pulmonary fibrotic disorders.

Keywords: bleomycin, connective tissue growth factor, fibroblasts, pasireotide, transforming growth factor beta

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