Publications

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    ABSTRACT: Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
    Science translational medicine 08/2013; 5(200):200ra117. · 10.76 Impact Factor
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    ABSTRACT: Mechanical ventilation (MV) with O(2)-rich gas (MV-O(2)) offers life-saving treatment for newborn infants with respiratory failure, but it also can promote lung injury, which in neonates translates to defective alveolar formation and disordered lung elastin, a key determinant of lung growth and repair. Prior studies in preterm sheep and neonatal mice showed that MV-O(2) stimulated lung elastase activity, causing degradation and remodeling of matrix elastin. These changes yielded an inflammatory response, with TGF-β activation, scattered elastic fibers, and increased apoptosis, culminating in defective alveolar septation and arrested lung growth. To see whether sustained inhibition of elastase activity would prevent these adverse pulmonary effects of MV-O(2), we did studies comparing wild-type (WT) and mutant neonatal mice genetically modified to express in their vascular endothelium the human serine elastase inhibitor elafin (Eexp). Five-day-old WT and Eexp mice received MV with 40% O(2) (MV-O(2)) for 24-36 h. WT and Eexp controls breathed 40% O(2) without MV. MV-O(2) increased lung elastase and MMP-9 activity, resulting in elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 increased 6-fold), apoptosis (cleaved-caspase-3 increased 10-fold), and inflammation (NF-κB activation, influx of neutrophils and monocytes) in lungs of WT vs. unventilated controls. These changes were blocked or blunted during MV-O(2) of Eexp mice. Scattered lung elastin and emphysematous alveoli observed in WT mice after 36 h of MV-O(2) were attenuated in Eexp mice. Both WT and Eexp mice showed defective VEGF signaling (decreased lung VEGF-R2 protein) and loss of pulmonary microvessels after lengthy MV-O(2), suggesting that elafin's beneficial effects during MV-O(2) derived primarily from preserving matrix elastin and suppressing lung inflammation, thereby enabling alveolar formation during MV-O(2). These results suggest that degradation and remodeling of lung elastin can contribute to defective lung growth in response to MV-O(2) and might be targeted therapeutically to prevent ventilator-induced neonatal lung injury.
    AJP Lung Cellular and Molecular Physiology 06/2012; 303(3):L215-27. · 3.52 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is an incurable disease associated with viral infections and connective tissue diseases. The relationship between inflammation and disease pathogenesis in these disorders remains poorly understood. To determine whether immune dysregulation due to absent T-cell populations directly contributes to the development of PAH. Vascular endothelial growth factor receptor 2 (VEGFR2) blockade induced significant pulmonary endothelial apoptosis in T-cell-deficient rats but not in immune-reconstituted (IR) rats. T cell-lymphopenia in association with VEGFR2 blockade resulted in periarteriolar inflammation with macrophages, and B cells even prior to vascular remodeling and elevated pulmonary pressures. IR prevented early inflammation and attenuated PAH development. IR with either CD8 T cells alone or with CD4-depleted spleen cells was ineffective in preventing PAH, whereas CD4-depleting immunocompetent euthymic animals increased PAH susceptibility. IR with either CD4(+)CD25(hi) or CD4(+)CD25(-) T cell subsets prior to vascular injury attenuated the development of PAH. IR limited perivascular inflammation and endothelial apoptosis in rat lungs in association with increased FoxP3(+), IL-10- and TGF-β-expressing CD4 cells, and upregulation of pulmonary bone morphogenetic protein receptor type 2 (BMPR2)-expressing cells, a receptor that activates endothelial cell survival pathways. PAH may arise when regulatory T-cell (Treg) activity fails to control endothelial injury. These studies suggest that regulatory T cells normally function to limit vascular injury and may protect against the development of PAH.
    Circulation Research 08/2011; 109(8):867-79. · 11.86 Impact Factor
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    Rasa Tamosiuniene, Mark R Nicolls
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    ABSTRACT: Pulmonary hypertension (PH) is a disease of high lethality arising from numerous causes. For a significant subset of PH patients, autoimmune biomarkers or frank autoimmune disease are simultaneously present, but the extent to which lung inflammation contributes to PH is unknown. However, emerging experimental and clinical evidence suggests that immune dysregulation may lead to the propagation of vascular injury and PH. A recent preclinical study demonstrated that regulatory T cells are important mediators normally enlisted to control inflammation and that, if absent or dysfunctional, may predispose to the development of PH.
    Trends in cardiovascular medicine 08/2011; 21(6):166-71. · 4.37 Impact Factor
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    ABSTRACT: Mechanical ventilation with O₂-rich gas (MV-O₂) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-β activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease. To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O₂-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest. Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O₂ for 8-24 hours; control animals breathed 40% O₂ without MV. At study's end, lungs were harvested to assess key variables noted below. MV-O₂ of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O₂-induced changes. Intratracheal elafin, by blocking lung protease activity, prevented MV-O₂-induced elastin degradation, TGF-β activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O₂. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O₂ and might be targeted therapeutically to prevent MV-O₂-induced lung injury.
    American Journal of Respiratory and Critical Care Medicine 05/2011; 184(5):537-46. · 11.04 Impact Factor
  • 09/2009: pages 417 - 436; , ISBN: 9780470747490
  • Clinical Immunology - CLIN IMMUNOL. 01/2009; 131.
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    ABSTRACT: Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobaric-hypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 +/- 1.4 versus 13.8 +/- 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 +/- 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B(2) excretion increased following hypoxia (44.6 +/- 11.1 versus 14.7 +/- 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 +/- 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin(1alpha) excretion following hypoxia was reduced by COX-2 gene disruption (29 +/- 3 versus 52 +/- 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA(2)/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA(2), and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.
    Journal of Pharmacology and Experimental Therapeutics 08/2008; 326(1):51-8. · 3.89 Impact Factor
  • Rasa Tamosiuniene, Xinguo Jiang, Mark Nicolls
    Clinical Immunology - CLIN IMMUNOL. 01/2008; 127.
  • Mark R. Nicolls, Rasa Tamosiuniene
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    ABSTRACT: The immunoglobulin supergene family (IgSF) cell adhesion molecules (CAMs) are either homophilic or heterophilic proteins that bind either integrins or different IgSF CAMs. Proteins are classified into the IgSF if they possess a structural domain known as an Ig domain, which contain about 70–110 amino acids and are categorized into different types according to their size and function [1]. Members of this family with important adhesion function include CD2, CD48, the SIGLEC family (sialic acid binding Ig-like lectins such as CD22, CD83), intracellular adhesion molecules (ICAMs), vascular cell adhesion molecule (VCAM-1), platelet-endothelial cell adhesion molecule (PECAM-1), neural cell adhesion molecules (NCAMs), L1-CAM and CHL-1. NCAMs, L1-CAM and CHL-1 are important proteins for neurological cell adhesion. Members of the IgSF are ligands for the integrins, and so these can be considered together conceptually with this class of CAMs. IgSF members have not been as extensively targeted as have integrin proteins, and the broad utility of these agents are largely undetermined. A summary of selected pre-clinical studies and clinical trials is presented in Table 1. Anti-ICAM therapy has proven neutral or possibly deleterious in a stroke trial [2]. Anti-CD2 therapy has shown efficacy against graft vs. host disease [3], but this is likely due to lymphocyte and natural killer cell depletion rather than anti-adhesion effects.
    12/2007: pages 107-128;
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    ABSTRACT: Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia. Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1+/-3.2 versus 17.2+/-3.1 mm Hg; n=8, P<0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8+/-5.9 mm Hg; n=8, P<0.05), an effect that was attenuated by the thromboxane (TX) A2/prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB2 increased during hypoxia (5.9+/-0.9 versus 1.2+/-0.2 ng/mg creatinine; n=6, P<0.01) and was further increased by COX-2 inhibition (8.5+/-0.7 ng/mg creatinine; n=6, P< 0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F1alpha decreased with COX-2 inhibition (8.6+/-3.0 versus 27.0+/-4.8 ng/mg creatinine; n=6, P< 0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the COX-2 gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of COX-1 had no effect. COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxia-induced pulmonary hypertension.
    Circulation 11/2004; 110(17):2701-7. · 15.20 Impact Factor
  • Mark R. Nicolls, Rasa Tamosiuniene, Norbert F. Voelkel

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