title: Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism.
abstract: BACKGROUND
  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.
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Zuhal
authors.initials: Z
authors.lastname: Dincer
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Birgit
authors.initials: B
authors.lastname: Bollbuck
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Janet
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Beerli
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Gina
authors.initials: G
authors.lastname: Fishli-Cavelti
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nahler
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Angst
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Janser
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Heike
authors.initials: H
authors.lastname: Otto
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rosner
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Rene
authors.initials: R
authors.lastname: Hersperger
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Bruns
authors.affiliation: Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Quancard
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000814:Aniline Compounds; D004151:Dipeptides; D008246:Lysophospholipids; C000589382:NIBR-0213; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine