Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism
| Autor: | Daniela Angst, Nicolau Beckmann, Christian Bruns, Philipp Janser, Heike Otto, Jean Quancard, Marc Bigaud, Elisabeth Rosner, Birgit Bollbuck, Gina Fishli-Cavelti, Christian Beerli, Zuhal Dincer, Rene Hersperger, Michaela Nahler, Janet Dawson |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Pathology Respiratory System Vascular Permeability lcsh:Medicine Vascular permeability Pharmacology Pathology and Laboratory Medicine Vascular Medicine Diagnostic Radiology 0302 clinical medicine Sphingosine Fibrosis Edema Medicine and Health Sciences Homeostasis lcsh:Science Lung Immune Response Cells Cultured Tidal volume Aniline Compounds Multidisciplinary Radiology and Imaging Heart Dipeptides Thorax Magnetic Resonance Imaging Receptors Lysosphingolipid medicine.anatomical_structure 030220 oncology & carcinogenesis Pleura Anatomy medicine.symptom Signal Transduction Research Article medicine.medical_specialty Endothelium Imaging Techniques Immunology Inflammation Research and Analysis Methods Capillary Permeability 03 medical and health sciences Signs and Symptoms Adjuvants Immunologic Rheumatology Diagnostic Medicine medicine Animals Rats Wistar business.industry Arthritis lcsh:R Biology and Life Sciences medicine.disease Arthritis Experimental Rats 030104 developmental biology Rats Inbred Lew Cardiovascular Anatomy lcsh:Q Endothelium Vascular Lysophospholipids Lungs business |
| Zdroj: | PLoS ONE, Vol 11, Iss 12, p e0168252 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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