M Kathryn Steiner's scientific contributions

Publications (5)

  • Source
    M Kathryn Steiner · Ioana R Preston · James R Klinger · Nicholas S Hill
    Abstract: Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate intracellular cGMP are now emerging as promising, safe, and easy to administer therapies for pulmonary hypertension, with relatively few side effects. Recent studies have shown that PDE5 inhibitors are potent acute pulmonary vasodilators in experimental models that partially reverse established pulmonary arterial hypertension and blunt chronic pulmonary hypertension. In addition, studies on animals reveal that PDE5... Show More
    Full-text available · Article · Jul 2005 · Current Opinion in Pharmacology
  • Abstract: We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH). Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months. Ten... Show More
    Article · Dec 2006 · Chest
  • Source
    M Kathryn Steiner · Ioana R Preston
    Abstract: Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientific research has shown that endothelin-1 (ET-1) is overexpressed in several forms of pulmonary vascular disease and may play an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) improved exercise capacity, functional status, pulmonary hemodynamics, and delayed the time to clinical... Show More
    Full-text available · Article · Feb 2008 · Vascular Health and Risk Management
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    Todd Hirschtritt · M. Kathryn Steiner · Nicholas S. Hill
    Abstract: Pulmonary arterial hypertension (PAH) is a progressive and often fatal disease. Currently available pharmacotherapies are often suboptimal when used singly, due to either a poor clinical response or a complication from the therapy. As a consequence, transitioning patients from one therapy to another or adding a therapy is a frequently encountered clinical conundrum. This chapter examines the rationale and limited data surrounding transitioning patients from one pharmacotherapy to another... Show More
    Full-text available · Chapter · May 2008
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    Marcia Kathryn Steiner · Olga L Syrkina · Narasaish Kolliputi · Eugene J Mark · Aaron B Waxman
    Abstract: Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6-overexpressing transgenic mice (Tg(+)) and compared to wild-type (Tg(-)) controls in both normoxic and chronic hypoxic... Show More
    Full-text available · Article · Jan 2009 · Circulation Research

Publications citing this author (362)

    • However, only a small portion (20%) of these mice developed mild PH with scarce occlusive lesions. Previously, Steiner et al. have shown occlusive vascular remodeling in transgenic mice overexpressing IL-6 following 3-weeks exposure to hypoxia but not under normoxic conditions [7,14]. Although these models are helpful for us to understand the mechanisms that regulate pulmonary vascular remodeling, none of them fully resembles the pathology of clinical PAH.
    [Show abstract] [Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a lung vascular disease characterized with a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling resulting in right heart failure and premature death. In this brief review, we document the recent advances in identifying genetically modified murine models of PH, with a focus on the recent discovery of the mouse model of Tie2Cre-mediated deletion of prolyl hydroxylase 2, which exhibits progressive obliterative vascular remodeling, severe PAH, and right heart failure, thus recapitulating many of the features of clinical PAH. We will also discuss the translational potential of recent findings arising from experimental studies of murine PH models.
    Full-text · Article · Dec 2016
    • Indeed, interactions have been described between the plasma coagulation system and the endothelium, the cells that are in direct contact with plasma [7– 9]. Specifically, FXa and thrombin have been reported to exert direct effects on endothelial cells including activation, angiogenesis , vascular leakage and inflammation78921]. In line with this, thrombin has been shown to have a physiological role in modulating vascular tone by activating endothelial cells independent of its procoagulant properties [15,54,55].
    [Show abstract] [Hide abstract] ABSTRACT: A potential role for coagulation factors in pulmonary arterial hypertension has been recently described, but the mechanism of action is currently not known. Here, we investigated the interactions between thrombin and the nitric oxide-cGMP pathway in pulmonary endothelial cells and experimental pulmonary hypertension. Chronic treatment with the selective thrombin inhibitor melagatran (0.9 mg/kg daily via implanted minipumps) reduced right ventricular hypertrophy in the rat monocrotaline model of experimental pulmonary hypertension. In vitro, thrombin was found to have biphasic effects on key regulators of the nitric oxide-cGMP pathway in endothelial cells (HUVECs). Acute thrombin stimulation led to increased expression of the cGMP-elevating factors endothelial nitric oxide synthase (eNOS) and soluble guanylate cyclase (sGC) subunits, leading to increased cGMP levels. By contrast, prolonged exposition of pulmonary endothelial cells to thrombin revealed a characteristic pattern of differential expression of the key regulators of the nitric oxide-cGMP pathway, in which specifically the factors contributing to cGMP elevation (eNOS and sGC) were reduced and the cGMP-hydrolyzing PDE5 was elevated (qPCR and Western blot). In line with the differential expression of key regulators of the nitric oxide-cGMP pathway, a reduction of cGMP by prolonged thrombin stimulation was found. The effects of prolonged thrombin exposure were confirmed in endothelial cells of pulmonary origin (HPAECs and HPMECs). Similar effects could be induced by activation of protease-activated receptor-1 (PAR-1). These findings suggest a link between thrombin generation and cGMP depletion in lung endothelial cells through negative regulation of the nitric oxide-cGMP pathway, possibly mediated via PAR-1, which could be of relevance in pulmonary arterial hypertension.
    Full-text · Article · Jun 2013
    • sitaxsentan and ambrisentan, two selective ET A antagonists already marketed, have shown lower development of abnormal liver function [52].
    [Show abstract] [Hide abstract] ABSTRACT: Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
    Article · Jun 2016
    • ng/kg/min). We base the latter recommendation on the PKs of inhaled treprostinil and the effective Cmax achieved with the maximal dose of inhaled therapy as well as prior clinical studies in transitioning from IV prostacyclin to oral bosentan, in which the likelihood of successful transition was higher than in those on lower doses of prostacylcin. [19] Patients being considered for transition should also have experienced major complications of parenteral prostacyclin therapy such as sepsis, recurrent abscesses, intractable infusion site pain, or inability to appropriately manage the infusion system. Transition, if contemplated, should be made in the hospital setting at an experienced
    [Show abstract] [Hide abstract] ABSTRACT: Treprostinil is a potent prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization Group I). Previously, treprostinil was available only in subcutaneous (SC) or intravenous (IV) formulations. Availability of an inhaled formulation of treprostinil has provided clinicians with an alternative to continuous SC or IV treprostinil in appropriate patients. Stable PAH patients whose quality of life has been dramatically impacted by side effects of parenteral therapy or those who have had recurrent, life-threatening bloodstream infections but are otherwise responding well to treatment may be the candidates for continuing prostacyclin therapy with inhaled treprostinil. However, there is little clinical experience with transitioning patients from parenteral to inhaled treprostinil. We present the results of two cases that highlight important considerations in transitioning patients from parenteral to inhaled therapy, including the pharmacologic and clinical equivalence of formulations, dose titration of formulations and suggested criteria for patient selection.
    Full-text · Article · Apr 2013