Modulation of bleomycin induced lung fibrosis by serotonin receptor antagonists in mice

¹ Inserm, unit 700; Université Paris 7, Faculté de Médecine Denis Diderot, Assistance Publique Hôpitaux de Paris, Hôpital Bichat; and Service d'Anatomie Pathologique, et
² Inserm, unit 700; Université Paris 7, Faculté de Médecine Denis Diderot, Assistance Publique Hôpitaux de Paris, Hôpital Bichat
³ Inserm, unit 700; Université Paris 7, Faculté de Médecine Denis Diderot, Assistance Publique Hôpitaux de Paris, Hôpital Bichat; and Service de Pneumologie
⁴ Inserm, unit 700; Université Paris 7, Faculté de Médecine Denis Diderot, Assistance Publique Hôpitaux de Paris, Hôpital Bichat; and Laboratoire de Biochimie A
⁵ Hôpital Lariboisière Service de Biochimie.
⁶ Service d'Anatomie Pathologique, et

^* To whom correspondence should be addressed. E-mail: aurelie_fabre{at}yahoo.fr.

	Abstract

Serotonin (5 hydroxytryptamine, 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes (5-HT2A and 5-HT2B) have been shown to play the most important role in the lung.

We investigated the role of serotonin in lung fibrosis using the bleomycin mouse model of lung fibrosis.

Serotonin concentrations in lung homogenates significantly increased over the time course of bleomycin induced fibrosis, with a maximum at day 7. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors (by ketanserin) and 5-HT2B receptors (by SB215505) reduced bleomycin-induced lung fibrosis as assessed by reduced lung collagen contents and procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an anti-fibrotic environment through the decrease of lung TGF-beta1, CTGF and PAI-1 mRNA but they had minimal effects on lung inflammation as assessed by BAL cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples.

We conclude that serotonin is involved in the pathophysiology of bleomycin-induced lung fibrosis in mice and may be identified as a therapeutic target in lung fibrotic disorders.