10 research outputs found
Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism
<div><p>Rational</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div
NIBR-0213-induced vascular leakage in the lungs evaluated by MRI.
<p><b>(A)</b> Axial MRI sections through the chest of one animal at approximately the same anatomical location acquired before (baseline) and at different time points with respect to beginning of treatment with NIBR-0213 (30 mg/kg BID). The white and red arrows display fluid signals in the lungs and the pleura, respectively, elicited by the compound. <b>(B)</b> Differential MRI signal volumes (mean ± s.e.m; n = 4–8) in the lungs and pleura. For the lungs, differential volumes (<i>i</i>.<i>e</i>. baseline-subtracted) are presented. <b>(C)</b> MRI signals (means ± s.e.m, n = 3) in the lungs and pleura at 24 h and 96 h after beginning of treatment with NIBR-0213 (3, 10 or 30 mg/kg BID) or FTY720 (1 mg/kg QD). For the lungs, differential signal volumes (<i>i</i>.<i>e</i>. baseline-subtracted) are presented. * p<0.05.</p
Chronic microscopic changes provoked by NIBR-0213 in rat lungs.
<p>An overview of chronic changes with alveolar degeneration /regeneration and accumulation of macrophages (<b>A:</b> 10X, H&E.) and of fibrotic foci (<b>B:</b> 12X, H&E.) observed in the lungs of a rat treated orally over 2 weeks with NIBR-0213 at 300 and 100 mg/kg QD, respectively.</p
Acute microscopic changes provoked by NIBR-0213 in rat lungs.
<p>An overview of acute inflammatory changes (<b>A:</b> 4X, H&E) and of perivascular/alveolar/interstitial edema (<b>B</b>: 8X, H&E) observed in the lungs of rats treated orally over 2 week with NIBR-0213 at 100 or 300 mg/kg QD, respectively.</p
Macroscopic changes provoked by NIBR-0213 treatments in rats.
<p>Changes in bodyweight <b>(A)</b> and organ weight <b>(B)</b> of rats (males or females) treated orally with NIBR-0213 at 30, 100 or 300 mg/kg QD, or its vehicle, during 2 weeks. The mean body and organ weights measured in each groups at termination are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168252#pone.0168252.s003" target="_blank">S3 Table</a>. Results are mean ± s.e.m. (n = 4–5/group/sex). * p<0.05.</p
Acute microscopic changes provoked by NIBR-0213 in rat hearts.
<p>Perivascular edema (<b>A:</b> 20X, H&E.) and focal degenerative myocytes with interstitial inflammatory cells and fibrosis (<b>B:</b> 20X, H&E.) observed in the hearts of a rat treated orally over 2 weeks with NIBR-0213 at 100 mg/kg QD.</p
Microscopic findings in lungs and heart of rats treated with NIBR-0213.
<p>Incidence (%) and mean severity (GRADES: 1 = minimal/very few and small; 2 = slight/few/small; 3 = moderate/moderate number and size; 4 = marked/many/large) of the microscopic findings in lungs and heart of rats treated with NIBR-0213. The individual severity GRADES are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168252#pone.0168252.s004" target="_blank">S4 Table</a>.</p
Inhibitory efficacy of NIBR-0213 in a rat AiA model.
<p>Inhibition of paw swelling (as measured at day 12 post-adjuvant challenge) in the rat AiA model in response to oral treatments with NIBR-0213 (30 mg/kg BID, n = 10/group) or FTY720 (0.1 mg/kg QD, n = 5/group), starting at either 5 or 9 days post-challenge with Freund Adjuvant. Individual mean mØ and ΔmØ values are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168252#pone.0168252.s001" target="_blank">S1 Table</a>.</p