Current Role at Stanford

University Staff - Basic Life Research Associate
Medicine - Med/Pulmonary and Critical Care Medicine


Professional Interests

Pulmonary Hypertension
Cardiovascular Medicine
Pulmonary Medicine
Vascular Biology


All Publications

  • Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation Saito, T., Miyagawa, K., Chen, S. Y., Tamosiuniene, R., Wang, L., Sharp, O., Samayoa, E., Harada, D., Moonen, J. A., Cao, A., Chen, P. I., Hennigs, J. K., Gu, M., Li, C. G., Leib, R. D., Li, D., Adams, C. M., Del Rosario, P. A., Bill, M. A., Haddad, F., Montoya, J. G., Robinson, W., Fantl, W. J., Nolan, G. P., Zamanian, R. T., Nicolls, M. R., Chiu, C. Y., Ariza, M. E., Rabinovitch, M. 2017


    Background -Immune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue and elevated cytokines have been related to PAH pathogenesis but without clear understanding of how these abnormalities are initiated, perpetuated and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies. Methods -Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next generation sequencing, functional studies in cultured monocytes and endothelial cells (EC) and hemodynamic and lung studies in a rat. Results -SAM domain and HD1 domain-containing protein (SAMHD1), an innate immune factor that suppresses HIV replication was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), perivascular dendritic cells and macrophages and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1? and TNF?) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6. Conclusions -Our study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

    View details for DOI 10.1161/CIRCULATIONAHA.117.027589

    View details for PubMedID 28935667

  • Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert review of cardiovascular therapy Voelkel, N. F., Tamosiuniene, R., Nicolls, M. R. 2016; 14 (8): 939-951


    Inflammatory cells are present in the lungs from patients with many, if not all, forms of severe pulmonary hypertension. Historically the first inflammatory cell identified in the pulmonary vascular lesions was the mast cell. T and B lymphocytes, as well as macrophages, are present in and around the pulmonary arterioles and many patients have elevated blood levels of interleukin 1 and 6; some patients show elevated levels of leukotriene B4. An overlap between collagen-vascular disease-associated pulmonary arterial hypertension (PAH) and idiopathic PAH exists, yet only a few studies have been designed that evaluate the effect of anti-inflammatory treatments. Here we review the pertinent data that connect PAH and inflammation/immune dysregulation and evaluate experimental models of severe PAH with an emphasis on the Sugen/athymic rat model of severe PAH. We postulate that there are more than one inflammatory phenotype and predict that there will be several anti-inflammatory treatment strategies for severe PAH.

    View details for DOI 10.1080/14779072.2016.1180976

    View details for PubMedID 27096622

  • Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239


    A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

    View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

    View details for Web of Science ID 000364481400021

    View details for PubMedID 26558820

    View details for PubMedCentralID PMC4646718

  • Blocking Macrophage Leukotriene B-4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension SCIENCE TRANSLATIONAL MEDICINE Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200)
  • Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Hilgendorff, A., Parai, K., Ertsey, R., Rey-Parra, G. J., Thebaud, B., Tamosiuniene, R., Jain, N., Navarro, E. F., Starcher, B. C., Nicolls, M. R., Rabinovitch, M., Bland, R. D. 2012; 303 (3): L215-L227
  • Regulatory T Cells Limit Vascular Endothelial Injury and Prevent Pulmonary Hypertension CIRCULATION RESEARCH Tamosiuniene, R., Tian, W., Dhillon, G., Wang, L., Sung, Y. K., Gera, L., Patterson, A. J., Agrawal, R., Rabinovitch, M., Ambler, K., Long, C. S., Voelkel, N. F., Nicolls, M. R. 2011; 109 (8): 867-U120


    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-?-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.

    View details for DOI 10.1161/CIRCRESAHA.110.236927

    View details for Web of Science ID 000295368300008

    View details for PubMedID 21868697

  • Inhibiting Lung Elastase Activity Enables Lung Growth in Mechanically Ventilated Newborn Mice AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Hilgendorff, A., Parai, K., Ertsey, R., Jain, N., Navarro, E. F., Peterson, J. L., Tamosiuniene, R., Nicolls, M. R., Starcher, B. C., Rabinovitch, M., Bland, R. D. 2011; 184 (5): 537-546


    Mechanical ventilation with O?-rich gas (MV-O?) 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)-? 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-O?-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% O? for 8-24 hours; control animals breathed 40% O? without MV. At study's end, lungs were harvested to assess key variables noted below.MV-O? 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-? 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-O?-induced changes.Intratracheal elafin, by blocking lung protease activity, prevented MV-O?-induced elastin degradation, TGF-? activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O?. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O? and might be targeted therapeutically to prevent MV-O?-induced lung injury.

    View details for DOI 10.1164/rccm.201012-2010OC

    View details for Web of Science ID 000294478200014

    View details for PubMedID 21562133

    View details for PubMedCentralID PMC3175547

  • Regulatory T Cells and Pulmonary Hypertension TRENDS IN CARDIOVASCULAR MEDICINE Tamosiuniene, R., Nicolls, M. R. 2011; 21 (6): 166-171


    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.

    View details for Web of Science ID 000306942700003

    View details for PubMedID 22814424

  • Immune Reconstitution Prevents Autoimmune Inflammation and Right Ventricular Remodeling in Immunodeficiency-Associated Pulmonary Hypertension 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Tamosiuniene, R., Long, C., Ambler, K., Sung, Y., Gera, L., Wang, L., Nicolls, M. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1135?S1135
  • Prevention of Adverse Right Ventricular Remodeling and Autoimmune Inflammation after Splenocyte Therapy in Pulmonary Hypertension: Contribution of HOX11+, C-kit+, FOXP3+Cells 9th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Tamosiuniene, R., Long, C., Ambler, K., Wang, L., Gera, L., Sung, Y., Nicolls, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S69?S70
  • Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Cathcart, M., Tamosiuniene, R., Chen, G., Neilan, T. G., Bradford, A., O'Byrne, K. J., Fitzgerald, D. J., Pidgeon, G. P. 2008; 326 (1): 51-58


    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.

    View details for DOI 10.1124/jpet.107.134221

    View details for Web of Science ID 000256889300006

    View details for PubMedID 18375790

  • Intravascular thrombosis after hypoxia-induced pulmonary hypertension - Regulation by cyclooxygenase-2 CIRCULATION Pidgeon, G. P., Tamosiuniene, R., Chen, G., Leonard, I., Belton, O., Bradford, A., Fitzgerald, D. J. 2004; 110 (17): 2701-2707


    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.

    View details for DOI 10.1161/01.CIR.0000145613.01188.0B

    View details for Web of Science ID 000224699500024

    View details for PubMedID 15492320

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