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Pathophysiological consequences of a break in S1P1-dependent homeostasis of vascular permeability revealed by S1P1 competitive antagonism

Bigaud, Marc and Dincer, Zuhal and Bollbuck, Birgit and Dawson King, Janet and Beckmann, Nicolau and Beerli, Christian and Cavelti, Gina and Nahler, Michaela and Angst, Daniela and Janser, Philipp and Otto, Heike and Rosner, Elisabeth and Hersperger, Rene and Bruns, Christian and Quancard, Jean (2016) Pathophysiological consequences of a break in S1P1-dependent homeostasis of vascular permeability revealed by S1P1 competitive antagonism. PLOS ONE.

Abstract

Rational: Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist.

Results: NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant-induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3-4 days, as evidenced by MRI monitoring. At the supra-maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences.

Conclusions: Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates.

Item Type: Article
Keywords: NIBR-0213, vascular permeability
Date Deposited: 08 Dec 2016 00:45
Last Modified: 08 Dec 2016 00:45
URI: https://oak.novartis.com/id/eprint/25717

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