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Pellicano C, Oliva A, Colalillo A, Luceri C, Gigante A, Mastroianni CM, Tornese D, Carnazzo V, Basile V, Rosato E, Basile U. Markers of Endotoxemia and Inflammation are Associated with Digital Ulcers in Systemic Sclerosis Patients. Immunol Invest 2025:1-14. [PMID: 40099380 DOI: 10.1080/08820139.2025.2478932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
BACKGROUND The aim of this study was to evaluate the possible role of lipopolysaccharide-binding protein (LBP) and interleukin 6 (IL-6) in the development of digital ulcers (DUs) in Systemic sclerosis (SSc). METHODS 60 SSc patients were enrolled and tested for serum levels of LBP and IL-6. The development of DUs was assessed in a 12-month follow-up period. RESULTS Median LBP and IL-6 were 107.445 ng/mL and 10.8 pg/mL whilst 33.3% patients had LBP ≥ 11995 ng/mL and 51.7% patients had IL-6 ≥ 12.5 pg/mL. DUs history were present in 41.7% SSc patients and at follow-up 23.3% patients developed new DUs. Baseline LBP (14105 ng/mL vs 10355 ng/mL, p < .001) and IL-6 (195 pg/mL vs 9.4 ng/mL, p < .001) were higher in SSc patients with new DUs. The ROC curves showed a good diagnostic accuracy for a cut-off of LBP ≥ 11995 ng/mL [AUC = 0.804 (95% CI = 0.656-0.951), p < .001] and for a cut-off of IL-6 ≥ 12.5 pg/mL [AUC = 0.897 (95% CI = 0.783-1.000), p < .001]. Free survival from new DUs was shorter in SSc patients with increased LBP (p < .001) or IL-6 (p = .003). CONCLUSIONS LPB or IL-6 could play a role in digital microvascular damage of SSc patients.
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Affiliation(s)
- Chiara Pellicano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Amalia Colalillo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Cristina Luceri
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Antonietta Gigante
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Daniela Tornese
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
| | - Valeria Carnazzo
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
| | - Valerio Basile
- Clinical Pathology Unit and Cancer Biobank, Department of Research and Advanced Technologies, I.R.C.C.S. Regina Elena National Cancer Institute, Rome, Italy
| | - Edoardo Rosato
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Umberto Basile
- Dipartimento di Patologia Clinica, Ospedale Santa Maria Goretti, Latina, Italy
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Habbas AH, Abu-Raghif AR, Ridha-Salman H, Hussein MN. Therapeutic effect of bosentan on 2, 4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model. Arch Dermatol Res 2025; 317:436. [PMID: 39966154 DOI: 10.1007/s00403-025-03955-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/02/2025] [Accepted: 02/03/2025] [Indexed: 02/20/2025]
Abstract
Eczematous or atopic dermatitis (AD) is a chronic autoinflammatory skin disorder distinguished by severe itching, scratching, and erosion. Bosentan is an endothelin receptor antagonist with improved immunomodulatory and anti-inflammatory actions. This study aimed to assess the efficiency of topical bosentan in alleviating a 2, 4-dinitrochlorobenzene (DNCB)-induced mouse model of AD. 50 Swiss albino mice were haphazardly grouped into 5 teams of 10 each. The first week of the experiment involved DNCB sensitization on back skin mice, preceding a four-week DNCB challenge to induce AD-like skin inflammation. The control group gets no treatment. The induction group administered DNCB only. Starting two hours after the second sensitization, the vehicle group received topical vehicle solution, the bosentan group received 5% bosentan ointment, and the tacrolimus group received 0.1% tacrolimus ointment once daily for a period of four weeks. Topical bosentan markedly mitigated DNCB-aggravated AD-like skin lesions, as displayed by decreased total dermatitis scores and lowering the upregulated counts of total leukocytes, neutrophils, lymphocytes, monocytes, and eosinophils. Additionally, bosentan dramatically alleviated interleukin (IL)-4 and IL-13 immunohistochemistry scores, as well as IL-1β, IL-6, IL-17, TNFα, and IFN-γ epidermal levels. In conclusion, Bosentan treatment also significantly diminished levels of immunoglobulin E (IgE) and oxidative biomarker malondialdehyde (MDA) and histopathology scores, notably epidermal thickness and inflammation. Bosentan mitigates the severity of DNCB-induced AD-like skin inflammation, possibly owing to its potent anti-inflammatory and immunomodulatory properties.
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Affiliation(s)
| | | | | | - Muataz Naeem Hussein
- College of Medicine, Department of Pharmacology, Al-Nahrain University, Baghdad, Iraq
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3
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Tsai J, Malik S, Tjen-A-Looi SC. Pulmonary Hypertension: Pharmacological and Non-Pharmacological Therapies. Life (Basel) 2024; 14:1265. [PMID: 39459565 PMCID: PMC11509317 DOI: 10.3390/life14101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Pulmonary hypertension (PH) is a severe and chronic disease characterized by increased pulmonary vascular resistance and remodeling, often precipitating right-sided heart dysfunction and death. Although the condition is progressive and incurable, current therapies for the disease focus on multiple different drugs and general supportive therapies to manage symptoms and prolong survival, ranging from medications more specific to pulmonary arterial hypertension (PAH) to exercise training. Moreover, there are multiple studies exploring novel experimental drugs and therapies including unique neurostimulation, to help better manage the disease. Here, we provide a narrative review focusing on current PH treatments that target multiple underlying biochemical mechanisms, including imbalances in vasoconstrictor-vasodilator and autonomic nervous system function, inflammation, and bone morphogenic protein (BMP) signaling. We also focus on the potential of novel therapies for managing PH, focusing on multiple types of neurostimulation including acupuncture. Lastly, we also touch upon the disease's different subgroups, clinical presentations and prognosis, diagnostics, demographics, and cost.
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Affiliation(s)
- Jason Tsai
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
| | | | - Stephanie C. Tjen-A-Looi
- Susan Samueli Integrative Health Institute, College of Health Sciences, University of California-Irvine, Irvine, CA 92617, USA;
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Uzun N, Durmus S, Gercel G, Aksu B, Misirlioglu NF, Uzun H. Effects of Bosentan on Hypoxia, Inflammation and Oxidative Stress in Experimental Blunt Thoracic Trauma Model. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1148. [PMID: 39064577 PMCID: PMC11278988 DOI: 10.3390/medicina60071148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/04/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: In this study, we aimed to investigate the effects of bosentan, an endothelin receptor antagonist, on endothelin-1 (ET-1), hypoxia-inducible factor-1 (HIF-1), nuclear factor-kappa B (NF-κB), and tumor necrosis factor (TNF)-α as inflammation markers, pro-oxidant antioxidant balance (PAB), and total antioxidant capacity (TAC) levels as oxidative stress parameters in lung tissues of rats in an experimental model of pulmonary contusion (PC) induced by blunt thoracic trauma. Materials and Methods: Thirty-seven male Sprague-Dawley rats were divided into five groups. C: The control group (n = 6) consisted of unprocessed and untreated rats. PC3 (n = 8) underwent 3 days of PC. PC-B3 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 3 days. The PC7 group (n = 7) underwent 7 days of PC, and PC-B7 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 7 days. Results: ET-1, NF-κB, TNF-α, HIF-1α, and PAB levels were higher, while TAC activity was lower in all groups compared with the control (p < 0.05). There was no significant difference in ET-1 and TNF-α levels between the PC-B3 and PC-B7 groups and the control group (p < 0.05), while NF-κB, HIF-1α, and PAB levels were still higher in both the PC-B3 and PC-B7 groups than in the control group. Bosentan decreased ET-1, NF-κB, TNF-α, HIF-1α, and PAB and increased TAC levels in comparison to the nontreated groups (p < 0.05). Conclusions: Bosentan decreased the severity of oxidative stress in the lungs and reduced the inflammatory reaction in rats with PC induced by blunt thoracic trauma. This suggests that bosentan may have protective effects on lung injury mechanisms by reducing hypoxia, inflammation, and oxidative stress. If supported by similar studies, bosentan can be used in both pulmonary and emergency clinics to reduce ischemic complications, inflammation, and oxidative stress in some diseases that may be accompanied by ischemia.
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Affiliation(s)
- Nedim Uzun
- Department of Emergency, Gaziosmanpaşa Training and Research Hospital, University of Health Sciences, Istanbul 34098, Turkey;
| | - Sinem Durmus
- Department of Medical Biochemistry, Faculty of Medicine, Katip Celebi University, Izmir 35620, Turkey;
| | - Gonca Gercel
- Department of Pediatric Surgery, Istanbul Medeniyet University Göztepe Training and Research Hospital, Istanbul 34730, Turkey; (G.G.); (B.A.)
| | - Burhan Aksu
- Department of Pediatric Surgery, Istanbul Medeniyet University Göztepe Training and Research Hospital, Istanbul 34730, Turkey; (G.G.); (B.A.)
| | - Naile Fevziye Misirlioglu
- Department of Biochemistry, Gaziosmanpaşa Training and Research Hospital, University of Health Sciences, Istanbul 34098, Turkey;
| | - Hafize Uzun
- Department of Medical Biochemistry, Faculty of Medicine, Istanbul Atlas University, Istanbul 34408, Turkey
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Yıldırım Uslu E, Gülkesen A, Akgol G, Alkan G, Poyraz AK, İlhan N. Serum Endothelin-1 Level Can Reflect the Degree of Lumbar Degeneration: A Cross-Sectional Study. Cureus 2024; 16:e59966. [PMID: 38854285 PMCID: PMC11162144 DOI: 10.7759/cureus.59966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2024] [Indexed: 06/11/2024] Open
Abstract
Background Endothelin-1 (ET-1) is an agent closely associated with inflammation and has recently been recognized as a significant factor in degenerative processes. This study aimed to investigate the correlation between serum ET-1 level and radiological and clinical manifestations of lumbar disc herniation (LDH) and intervertebral disc degeneration (IDD) pathologies. Methodology The study was conducted with 50 healthy controls and 50 LDH patients. The pain level of the patients was analyzed with the Visual Analog Scale (VAS), and their functionality was analyzed with the Oswestry Disability Index (ODI). The disc degeneration and disc herniation grades were determined using magnetic resonance imaging. Serum ET-1 levels of the participants were measured using the enzyme-linked immunosorbent assay method. Results ET-1 level was significantly higher in the patient group compared to the controls (p < 0.01). A positive correlation was determined between serum ET-1 level and Pfirrmann grade in the patient group (p < 0.01). No correlation was determined between the MacNab grade, VAS, and ODI scores and ET-1 (p = 0.397, p = 0.137, and p = 0.208, respectively). There was no significant difference between the serum ET-1 levels of the patients with or without neurological deficits (p = 0.312). Conclusions The correlation between the serum ET-1 levels and IDD grade suggested that the former could serve as a biomarker to determine the degree of degeneration in the future. However, further research is required to determine the underlying mechanisms.
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Affiliation(s)
- Emine Yıldırım Uslu
- Physical Medicine and Rehabilitation, Elazığ Fethi Sekin City Hospital, Elazig, TUR
| | - Arif Gülkesen
- Physical Medicine and Rehabilitation, Firat University, Elazig, TUR
| | - Gurkan Akgol
- Physical Medicine and Rehabilitation, Firat University Hospital, Elazig, TUR
| | - Gökhan Alkan
- Physical Medicine and Rehabilitation, Firat University, Elazig, TUR
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Moccaldi B, De Michieli L, Binda M, Famoso G, Depascale R, Perazzolo Marra M, Doria A, Zanatta E. Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 24:ijms24044178. [PMID: 36835590 PMCID: PMC9967966 DOI: 10.3390/ijms24044178] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening complication of connective tissue diseases (CTDs) characterised by increased pulmonary arterial pressure and pulmonary vascular resistance. CTD-PAH is the result of a complex interplay among endothelial dysfunction and vascular remodelling, autoimmunity and inflammatory changes, ultimately leading to right heart dysfunction and failure. Due to the non-specific nature of the early symptoms and the lack of consensus on screening strategies-except for systemic sclerosis, with a yearly transthoracic echocardiography as recommended-CTD-PAH is often diagnosed at an advanced stage, when the pulmonary vessels are irreversibly damaged. According to the current guidelines, right heart catheterisation is the gold standard for the diagnosis of PAH; however, this technique is invasive, and may not be available in non-referral centres. Hence, there is a need for non-invasive tools to improve the early diagnosis and disease monitoring of CTD-PAH. Novel serum biomarkers may be an effective solution to this issue, as their detection is non-invasive, has a low cost and is reproducible. Our review aims to describe some of the most promising circulating biomarkers of CTD-PAH, classified according to their role in the pathophysiology of the disease.
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Affiliation(s)
- Beatrice Moccaldi
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, 35128 Padova, Italy
| | - Laura De Michieli
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova University Hospital, 35128 Padova, Italy
| | - Marco Binda
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, 35128 Padova, Italy
| | - Giulia Famoso
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova University Hospital, 35128 Padova, Italy
| | - Roberto Depascale
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, 35128 Padova, Italy
| | - Martina Perazzolo Marra
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova University Hospital, 35128 Padova, Italy
| | - Andrea Doria
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, 35128 Padova, Italy
- Correspondence: ; Tel.: +39-0498212190
| | - Elisabetta Zanatta
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, 35128 Padova, Italy
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Roy B, Runa SA. SARS-CoV-2 infection and diabetes: Pathophysiological mechanism of multi-system organ failure. World J Virol 2022; 11:252-274. [PMID: 36188734 PMCID: PMC9523319 DOI: 10.5501/wjv.v11.i5.252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/25/2022] [Accepted: 08/01/2022] [Indexed: 02/05/2023] Open
Abstract
Since the discovery of the coronavirus disease 2019 outbreak, a vast majority of studies have been carried out that confirmed the worst outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with preexisting health conditions, including diabetes, obesity, hypertension, cancer, and cardiovascular diseases. Likewise, diabetes itself is one of the leading causes of global public health concerns that impose a heavy global burden on public health as well as socio-economic development. Both diabetes and SARS-CoV-2 infection have their independent ability to induce the pathogenesis and severity of multi-system organ failure, while the co-existence of these two culprits can accelerate the rate of disease progression and magnify the severity of the disease. However, the exact pathophysiology of multi-system organ failure in diabetic patients after SARS-CoV-2 infection is still obscure. This review summarized the organ-specific possible molecular mechanisms of SARS-CoV-2 and diabetes-induced pathophysiology of several diseases of multiple organs, including the lungs, heart, kidneys, brain, eyes, gastrointestinal system, and bones, and sub-sequent manifestation of multi-system organ failure.
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Affiliation(s)
- Bipradas Roy
- Department of Physiology, Wayne State University, Detroit, MI 48201, United States
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI 48202, United States
| | - Sadia Afrin Runa
- Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh
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8
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Hinchcliff M, Garcia-Milian R, Di Donato S, Dill K, Bundschuh E, Galdo FD. Cellular and Molecular Diversity in Scleroderma. Semin Immunol 2021; 58:101648. [PMID: 35940960 DOI: 10.1016/j.smim.2022.101648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
With the increasing armamentarium of high-throughput tools available at manageable cost, it is attractive and informative to determine the molecular underpinnings of patient heterogeneity in systemic sclerosis (SSc). Given the highly variable clinical outcomes of patients labelled with the same diagnosis, unravelling the cellular and molecular basis of disease heterogeneity will be crucial to predicting disease risk, stratifying management and ultimately informing a patient-centered precision medicine approach. Herein, we summarise the findings of the past several years in the fields of genomics, transcriptomics, and proteomics that contribute to unraveling the cellular and molecular heterogeneity of SSc. Expansion of these findings and their routine integration with quantitative analysis of histopathology and imaging studies into clinical care promise to inform a scientifically driven patient-centred personalized medicine approach to SSc in the near future.
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Affiliation(s)
- Monique Hinchcliff
- Yale School of Medicine, Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, USA.
| | | | - Stefano Di Donato
- Raynaud's and Scleroderma Programme, Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR Biomedical Research Centre, University of Leeds, UK
| | | | - Elizabeth Bundschuh
- Yale School of Medicine, Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, USA
| | - Francesco Del Galdo
- Raynaud's and Scleroderma Programme, Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR Biomedical Research Centre, University of Leeds, UK.
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Torres Crigna A, Link B, Samec M, Giordano FA, Kubatka P, Golubnitschaja O. Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine. EPMA J 2021; 12:265-305. [PMID: 34367381 PMCID: PMC8334338 DOI: 10.1007/s13167-021-00248-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.
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Affiliation(s)
- Adriana Torres Crigna
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Barbara Link
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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TLR4-Endothelin Axis Controls Syncytiotrophoblast Motility and Confers Fetal Protection in Placental Malaria. Infect Immun 2021; 89:e0080920. [PMID: 34061587 DOI: 10.1128/iai.00809-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pregnancy-associated malaria is often associated with adverse pregnancy outcomes. Placental circulatory impairments are an intriguing and unsolved component of malaria pathophysiology. Here, we uncovered a Toll-like receptor 4 (TLR4)-TRIF-endothelin axis that controls trophoblast motility and is linked to fetal protection during Plasmodium infection. In a cohort of 401 pregnancies from northern Brazil, we found that infection during pregnancy reduced expression of endothelin receptor B in syncytiotrophoblasts, while endothelin expression was only affected during acute infection. We further show that quantitative expression of placental endothelin and endothelin receptor B proteins are differentially controlled by maternal and fetal TLR4 alleles. Using murine malaria models, we identified placental autonomous responses to malaria infection mediated by fetally encoded TLR4 that not only controlled placental endothelin gene expression but also correlated with fetal viability protection. In vitro assays showed that control of endothelin expression in fetal syncytiotrophoblasts exposed to Plasmodium-infected erythrocytes was dependent on TLR4 via the TRIF pathway but not MyD88 signaling. Time-lapse microscopy in syncytiotrophoblast primary cultures and cell invasion assays demonstrated that ablation of TLR4 or endothelin receptor blockade abrogates trophoblast collective motility and cell migration responses to infected erythrocytes. These results cohesively substantiate the hypothesis that fetal innate immune sensing, namely, the TRL4-TRIF pathway, exerts a fetal protective role during malaria infection by mediating syncytiotrophoblast vasoregulatory responses that counteract placental insufficiency.
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Fukui Y, Nakamura K, Hirabayashi M, Miyagawa T, Toyama S, Omatsu J, Awaji K, Ikawa T, Norimatsu Y, Yoshizaki A, Sato S, Asano Y. Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis. Exp Dermatol 2021; 30:951-958. [PMID: 33682189 DOI: 10.1111/exd.14321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/23/2022]
Abstract
Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-β-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.
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Affiliation(s)
- Yuki Fukui
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kouki Nakamura
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Megumi Hirabayashi
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Takuya Miyagawa
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Toyama
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Jun Omatsu
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Kentaro Awaji
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tetsuya Ikawa
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yuta Norimatsu
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Ayumi Yoshizaki
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yoshihide Asano
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Srivastava AK, Chand Yadav T, Khera HK, Mishra P, Raghuwanshi N, Pruthi V, Prasad R. Insights into interplay of immunopathophysiological events and molecular mechanistic cascades in psoriasis and its associated comorbidities. J Autoimmun 2021; 118:102614. [PMID: 33578119 DOI: 10.1016/j.jaut.2021.102614] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023]
Abstract
Psoriasis is an inflammatory skin disease with complex pathogenesis and multiple etiological factors. Besides the essential role of autoreactive T cells and constellation of cytokines, the discovery of IL-23/Th17 axis as a central signaling pathway has unraveled the mechanism of accelerated inflammation in psoriasis. This has provided insights into psoriasis pathogenesis and revolutionized the development of effective biological therapies. Moreover, genome-wide association studies have identified several candidate genes and susceptibility loci associated with this disease. Although involvement of cellular innate and adaptive immune responses and dysregulation of immune cells have been implicated in psoriasis initiation and maintenance, there is still a lack of unifying mechanism for understanding the pathogenesis of this disease. Emerging evidence suggests that psoriasis is a high-mortality disease with additional burden of comorbidities, which adversely affects the treatment response and overall quality of life of patients. Furthermore, changing trends of psoriasis-associated comorbidities and shared patterns of genetic susceptibility, risk factors and pathophysiological mechanisms manifest psoriasis as a multifactorial systemic disease. This review highlights the recent progress in understanding the crucial role of different immune cells, proinflammatory cytokines and microRNAs in psoriasis pathogenesis. In addition, we comprehensively discuss the involvement of various complex signaling pathways and their interplay with immune cell markers to comprehend the underlying pathophysiological mechanism, which may lead to exploration of new therapeutic targets and development of novel treatment strategies to reduce the disastrous nature of psoriasis and associated comorbidities.
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Affiliation(s)
- Amit Kumar Srivastava
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Tara Chand Yadav
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Harvinder Kour Khera
- Tata Institute for Genetics and Society, Centre at InStem, Bangalore, 560065, Karnataka, India; Division of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093, United States
| | - Purusottam Mishra
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Navdeep Raghuwanshi
- Vaccine Formulation & Research Center, Gennova (Emcure) Biopharmaceuticals Limited, Pune, 411057, Maharashtra, India
| | - Vikas Pruthi
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India
| | - Ramasare Prasad
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, Uttarakhand, India.
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13
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Karmouty-Quintana H, Thandavarayan RA, Keller SP, Sahay S, Pandit LM, Akkanti B. Emerging Mechanisms of Pulmonary Vasoconstriction in SARS-CoV-2-Induced Acute Respiratory Distress Syndrome (ARDS) and Potential Therapeutic Targets. Int J Mol Sci 2020; 21:E8081. [PMID: 33138181 PMCID: PMC7662604 DOI: 10.3390/ijms21218081] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 10/25/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.
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Affiliation(s)
- Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Divisions of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | | | - Steven P. Keller
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Sandeep Sahay
- Co-Director, Pulmonary Vascular Diseases Center, The Methodist Hospital, Houston, TX 77030, USA;
| | - Lavannya M. Pandit
- Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Bindu Akkanti
- Divisions of Pulmonary, Critical Care and Sleep Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
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14
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Why not consider an endothelin receptor antagonist against SARS-CoV-2? Med Hypotheses 2020; 141:109792. [PMID: 32361169 PMCID: PMC7194813 DOI: 10.1016/j.mehy.2020.109792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
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15
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Odler B, Foris V, Gungl A, Müller V, Hassoun PM, Kwapiszewska G, Olschewski H, Kovacs G. Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach. Front Physiol 2018; 9:587. [PMID: 29971007 PMCID: PMC6018494 DOI: 10.3389/fphys.2018.00587] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/02/2018] [Indexed: 12/12/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.
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Affiliation(s)
- Balazs Odler
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Vasile Foris
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Anna Gungl
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Veronika Müller
- Department of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Paul M Hassoun
- Division of Pulmonary & Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Grazyna Kwapiszewska
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Horst Olschewski
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Gabor Kovacs
- Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.,Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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16
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Vona R, Giovannetti A, Gambardella L, Malorni W, Pietraforte D, Straface E. Oxidative stress in the pathogenesis of systemic scleroderma: An overview. J Cell Mol Med 2018; 22:3308-3314. [PMID: 29664231 PMCID: PMC6010858 DOI: 10.1111/jcmm.13630] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 03/11/2018] [Indexed: 01/23/2023] Open
Abstract
Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional manifestations include activation of the immune system and vascular injury. SSc causes disability and death as the result of end‐stage organ failure. Two clinical subsets of the SSc are accepted: limited cutaneous SSc (lc‐SSc) and diffuse cutaneous SSc (dc‐SSc). At present, the aetiology and pathogenesis of SSc remain obscure, and consequently, disease outcome is unpredictable. Numerous studies suggest that reactive oxidizing species (ROS) play an important role in the pathogenesis of scleroderma. Over the years, several reports have supported this hypothesis for both lc‐SSc and dc‐SSc, although the specific role of oxidative stress in the pathogenesis of vascular injury and fibrosis remains to be clarified. The aim of the present review was to report and comment the recent findings regarding the involvement and role of oxidative stress in SSc pathogenesis. Biomarkers proving the link between ROS and the main pathological features of SSc have been summarized.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Biomarkers Unit, Rome, Italy
| | | | | | - Walter Malorni
- Center for Gender-Specific Medicine, Biomarkers Unit, Rome, Italy
| | - Donatella Pietraforte
- Center for Gender-Specific Medicine, Biomarkers Unit, Rome, Italy.,Core Facilities, Istituto Superiore di Sanità, Rome, Italy
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17
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Jiang Y, Zeng Y, Huang X, Qin Y, Luo W, Xiang S, Sooranna SR, Pinhu L. Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model. Am J Physiol Lung Cell Mol Physiol 2016; 311:L1023-L1035. [PMID: 27765761 PMCID: PMC5206403 DOI: 10.1152/ajplung.00043.2016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 10/03/2016] [Indexed: 02/07/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.
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MESH Headings
- A549 Cells
- Active Transport, Cell Nucleus/drug effects
- Animals
- Cell Nucleus/drug effects
- Cell Nucleus/metabolism
- Disease Models, Animal
- Down-Regulation/drug effects
- Endothelin-1/metabolism
- Kidney/drug effects
- Kidney/pathology
- Lipopolysaccharides/pharmacology
- Liver/drug effects
- Liver/pathology
- Lung/drug effects
- Lung/metabolism
- Male
- NF-kappa B/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 1/agonists
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Phenylacetates/pharmacology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Respiratory Distress Syndrome/enzymology
- Respiratory Distress Syndrome/genetics
- Respiratory Distress Syndrome/pathology
- p38 Mitogen-Activated Protein Kinases/metabolism
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Affiliation(s)
- Yujie Jiang
- The First Clinical Medical College of Jinan University, Guangzhou, Guangdong Province, China
- Department of Respiratory Medicine
| | - Yi Zeng
- Department of Central Laboratory, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Xia Huang
- The First Clinical Medical College of Jinan University, Guangzhou, Guangdong Province, China
- Department of Respiratory Medicine
| | - Yueqiu Qin
- Department of Digestive, Youjiang Medical University for Nationalities, Baise, Guangxi, China; Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | | | - Shulin Xiang
- Department of Intensive Care Unit, the People's Hospital of Guangxi, Nanning, Guangxi, China
| | - Suren R Sooranna
- Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdon; and
| | - Liao Pinhu
- Department of Intensive Care Medicine, Youjiang Medical University for Nationalities, Baise, Guangxi, China
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18
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Asano Y. Is macitentan not a treatment option for digital ulcers in systemic sclerosis? ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:S6. [PMID: 27867974 DOI: 10.21037/atm.2016.08.67] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Yoshihide Asano
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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19
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Nakamura K, Asano Y, Taniguchi T, Minatsuki S, Inaba T, Maki H, Hatano M, Yamashita T, Saigusa R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki A, Miyagaki T, Sugaya M, Sato S. Serum levels of interleukin-18-binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis. J Dermatol 2016; 43:912-8. [PMID: 26777734 DOI: 10.1111/1346-8138.13252] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 11/04/2015] [Indexed: 11/28/2022]
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro-inflammatory cytokines to the development of SSc, but the role of interleukin (IL)-18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL-18-binding protein isoform a (IL-18BPa), a soluble decoy receptor for IL-18, by enzyme-linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL-18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL-18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL-18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL-18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL-18BPa levels with erythrocyte sedimentation rate and C-reactive protein were noted. These results suggest that the inhibition of IL-18 signaling by IL-18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.
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Affiliation(s)
- Kouki Nakamura
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihide Asano
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Taniguchi
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shun Minatsuki
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Toshiro Inaba
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisataka Maki
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaru Hatano
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Yamashita
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Saigusa
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yohei Ichimura
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takehiro Takahashi
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Toyama
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ayumi Yoshizaki
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Makoto Sugaya
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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20
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Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc 2015; 12:370-5. [PMID: 25615959 DOI: 10.1513/annalsats.201410-463oc] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
RATIONALE Inflammation is associated with symptoms in many chronic illnesses; however, this link has not been established in pulmonary arterial hypertension. OBJECTIVES The objective of this study was to investigate the association between inflammatory markers and quality of life-related symptoms in patients with pulmonary arterial hypertension. We hypothesized that higher circulating IL-6 and tumor necrosis factor-α levels would be associated with worse quality of life-related symptoms. METHODS We performed a secondary analysis using baseline and 3-month assessments of 62 subjects in a clinical trial of aspirin and simvastatin to determine the association between plasma IL-6 and tumor necrosis factor-α levels and the Medical Outcomes Study Short Form-36 subscales (pain, vitality, mental health). MEASUREMENTS AND MAIN RESULTS The mean age was 49.7±13.4 years; 87% were female. Higher IL-6 levels were significantly associated with lower Medical Outcomes Study Short Form-36 subscale scores, indicating worse bodily pain, vitality, and mental health (all P<0.01). Higher tumor necrosis factor-α levels were significantly associated with increased bodily pain, but better mental health scores. CONCLUSIONS IL-6 and tumor necrosis factor-α levels are associated with certain quality of life domains in patients with pulmonary arterial hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).
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21
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Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A. The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis. Arch Immunol Ther Exp (Warsz) 2014; 63:41-52. [PMID: 25288367 PMCID: PMC4289534 DOI: 10.1007/s00005-014-0310-1] [Citation(s) in RCA: 198] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2013] [Accepted: 07/18/2014] [Indexed: 12/12/2022]
Abstract
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.
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Affiliation(s)
- Agata Kowalczyk
- Chair of Experimental and Clinical Physiology, Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland,
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22
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Günther J, Kill A, Becker MO, Heidecke H, Rademacher J, Siegert E, Radić M, Burmester GR, Dragun D, Riemekasten G. Angiotensin receptor type 1 and endothelin receptor type A on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients. Arthritis Res Ther 2014; 16:R65. [PMID: 24612997 PMCID: PMC4060229 DOI: 10.1186/ar4503] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 01/22/2014] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Agonistic autoantibodies (Aabs) against the angiotensin II receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) have been identified in patients with systemic sclerosis (SSc). In our present study, we examined the expression of the AT1R and the ETAR in human immune cells and the pathological effects mediated through these receptors by their corresponding Aabs. METHODS Protein expression of AT1R and ETAR on peripheral blood mononuclear cells (PBMCs) from healthy individuals and SSc patients was analyzed using flow cytometry, and mRNA expression of both receptors in PBMCs from healthy donors was examined by real-time PCR. In addition, PBMCs from healthy donors were stimulated in vitro with affinity-purified immunoglobulin G (IgG) fractions from SSc patients positive for AT1R and ETAR Aabs, as well as with IgG from healthy donors serving as controls. Alterations in cell surface marker expression, cytokine secretion and chemotactic motility were analyzed using flow cytometry, enzyme-linked immunosorbent assays and chemotaxis assays, respectively. The results were correlated with the characteristics and clinical findings of the IgG donors. RESULTS Both AT1R and ETAR were expressed on PBMCs in humans. Protein expression of both receptors was decreased in SSc patients compared with that of healthy donors and declined during the course of disease. IgG fractions of SSc patients positive for AT1R and ETAR Aabs induced T-cell migration in an Aab level-dependent manner. Moreover, IgG of SSc patients stimulated PBMCs to produce more interleukin 8 (IL-8) and chemokine (C-C motif) ligand 18 (CCL18) than did the IgG of healthy donors. All effects were significantly reduced by selective AT1R and ETAR antagonists. Statistical analysis revealed an association of SSc-IgG induced high IL-8 concentrations with an early disease stage and of high CCL18 concentrations with lung fibrosis onset and vascular complications in the respective IgG donors. CONCLUSION In our present study, we could demonstrate the expression of both AT1R and ETAR on human peripheral T cells, B cells and monocytes. The decreased receptor expression in SSc patients, the inflammatory and profibrotic effects upon Aab stimulation of PBMCs in vitro and the associations with clinical findings suggest a role for Aab-induced activation of immune cells mediated by the AT1R and the ETAR in the pathogenesis or even the onset of the disease.
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23
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Chrobak I, Lenna S, Stawski L, Trojanowska M. Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2. J Cell Physiol 2013; 228:1774-83. [PMID: 23359533 DOI: 10.1002/jcp.24337] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 01/18/2013] [Indexed: 12/17/2022]
Abstract
Systemic sclerosis (SSc) is a complex disease characterized by vascular alterations, activation of the immune system and tissue fibrosis. Previous studies have implicated activation of the interferon pathways in the pathogenesis of SSc. The goal of this study was to determine whether interferon type I and/or type II could play a pathogenic role in SSc vasculopathy. Human dermal microvascular endothelial cells (HDMVECs) and fibroblasts were obtained from foreskins of healthy newborns. The RT Profiler PCR Array System was utilized to screen for EndoMT genes. Treatment with IFN-α or IFN-γ downregulated Fli1 and VE-cadherin. In contrast, IFN-α and IFN-γ exerted opposite effects on the expression of α-SMA, CTGF, ET-1, and TGFβ2, with IFN-α downregulating and IFN-γ upregulating this set of genes. Blockade of TGFβ signaling normalized IFN-γ-mediated changes in Fli1, VE-cadherin, CTGF, and ET-1 levels, whereas upregulation of α-SMA and TGFβ2 was not affected. Bosentan treatment was more effective than TGFβ blockade in reversing the actions of IFN-γ, including downregulation of α-SMA and TGFβ2, suggesting that activation of the ET-1 pathway plays a main role in the IFN-γ responses in HDMECs. IFN-γ induced expression of selected genes related to endothelial-to-mesenchymal transition (EndoMT), including Snail1, FN1, PAI1, TWIST1, STAT3, RGS2, and components of the WNT pathway. The effect of IFN-γ on EndoMT was mediated via TGFβ2 and ET-1 signaling pathways. This study demonstrates distinct effects of IFN-α and IFN-γ on the biology of vascular endothelial cells. IFN-γ may contribute to abnormal vascular remodeling and fibrogenesis in SSc, partially via induction of EndoMT.
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Affiliation(s)
- Izabela Chrobak
- Boston University School of Medicine, Arthritis Center, Boston, Massachusetts 02118, USA
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Tetè S, Varvara G, Murmura G, Saggini A, Maccauro G, Rosati M, Cianchetti E, Tripodi D, Toniato E, Fulcheri M, Caraffa A, Antinolfi P, Pandolfi F, Potalivo G, Conti P, Theoharides T. Impact of Immunity in Autism Spectrum Disorders. EUR J INFLAMM 2013. [DOI: 10.1177/1721727x1301100103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Autism spectrum disorders (ASDs) are childhood psychopathologies characterized by having difficulties in social interaction, verbal and non-verbal communication as well as sensor motor movements. Evidence suggests that in ASDs environmental toxicant exposure, genetic and mitochondrial dysfunction are involved associated with abnormal immune response with allergic problems and elevated serum IgE. ASDs present the major cytokine and chemokine dysfunction in CNS and is mediated by an increase of pro-inflammatory cytokine levels in the brain, such as TNF, IL-1, IFN-γ, IL-6, IL-8 and others. Mast cells, which are also implicated in ASDs, are worsened by stress and produce proinflammatory cytokines and can be stimulated by neurotensin in the brain and gut, contributing also to the inflammatory response. However, the exact etiology of ASDs remains largely unknown.
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Affiliation(s)
- S. Tetè
- Dental School, University of Chiet-Pescarai, Chieti, Italy
| | - G. Varvara
- Dental School, University of Chiet-Pescarai, Chieti, Italy
| | - G. Murmura
- Dental School, University of Chiet-Pescarai, Chieti, Italy
| | - A. Saggini
- Dermatology Department, University Tor Vergata, Rome, Italy
| | - G. Maccauro
- Orthopedics Division, Università Cattolica, Rome, Italy
| | - M. Rosati
- Gynecology Division, Pescara Hospital, Italy
| | - E. Cianchetti
- Department of Surgery, Ortona ASL Hospital, Ortona, Italy
| | - D. Tripodi
- Dental School, University of Chiet-Pescarai, Chieti, Italy
| | - E. Toniato
- Immunology Division, Medical School, University of Chieti-Pescara, Italy
| | - M. Fulcheri
- Psychology School, University of Chieti-Pescara, Italy
| | - A. Caraffa
- Orthopeadics Division, University of Perugia, Italy
| | - P. Antinolfi
- Orthopeadics Division, University of Perugia, Italy
| | - F. Pandolfi
- Department of Medicine, Catholic University of Rome, Rome, Italy
| | - G. Potalivo
- Orthopeadics Division, University of Perugia, Italy
| | - P. Conti
- Immunology Division, Medical School, University of Chieti-Pescara, Italy
| | - T.C. Theoharides
- Internal Medicine and Biochemistry, Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Drug Discovery Laboratory, Tufts-New England Medical Center, Boston, MA, USA
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Nicoletti M, Maccauro G, Tripodi D, Saggini A, Potalivo G, Castellani M, Conti F, Rosati M, Tomato E, Caraffa A, Antinolfi P, Conti P, Theoharides T. Impact of IL-33 on PGD2 Generation by Activated Human Cord Blood-Derived Mast Cell: Lack of Effect on Tryptase Release. EUR J INFLAMM 2012; 10:473-482. [DOI: 10.1177/1721727x1201000323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Mast cells are important not only in allergic reactions, but also in inflammation and are involved in a variety of responses including the immediate release of potent inflammatory mediators after activation by cross-linking of FcεRI molecules. Prostaglandin D2 (PGD2) is a major cyclooxygenase metabolite of arachidonic acid produced by mast cells and it is released following allergen challenge in allergic diseases. IL-33 is an iflammatory cytokine which is critically involved in the regulation of in vitro and in vivo cyclooxygenase production, providing a potential therapeutic target for inflammatory disorders. In this study, using human derived umbelical cord blood mast cells, we show that IL-33 (50 ng/ml), and calcium ionophore A 23187 (0.5 μg/ml), compound 48/80 (10−5 M) or anti-IgE (10 μg/ml), enhaced the production of PGD2 and this effect was inhibited by indomethacin. However, IL-33 was unable to induce tryptase release in these cells. These effects confirm the inflammatory property of IL-33 by stimulating PGD2 but not tryptase in human mast cells. The inhibitory effect of this new cytokine may have a potential therapeutic response in allergic and inflammatory diseases.
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Affiliation(s)
- M. Nicoletti
- Department of Neurosciences and Imaging, University of Chieti, Italy
| | - G. Maccauro
- Orthopedics Division, Catholic University of Rome, Rome, Italy
| | - D. Tripodi
- Dental School, University of Chieti-Pescara, Chieti, Italy
| | - A. Saggini
- Dermatology Department, University Tor Vergata, Rome, Italy
| | - G. Potalivo
- Orthopedics Division, University of Perugia, Perugia, Italy
| | - M.L. Castellani
- Immunology Division, University of Chieti-Pescara, Chieti, Italy
| | - F. Conti
- Gynecology Division, “Santo Spirito” Hospital, Pescara, Italy
| | - M. Rosati
- Gynecology Division, “Santo Spirito” Hospital, Pescara, Italy
| | - E. Tomato
- Immunology Division, University of Chieti-Pescara, Chieti, Italy
| | - A. Caraffa
- Orthopedics Division, University of Perugia, Perugia, Italy
| | - P. Antinolfi
- Orthopedics Division, University of Perugia, Perugia, Italy
| | - P. Conti
- Immunology Division, University of Chieti-Pescara, Chieti, Italy
| | - T.C. Theoharides
- Department of Physiology and Pharmacology, Tufts University School of Medicine, New England Medical Center, Boston, MA, USA
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Kohan DE, Cleland JG, Rubin LJ, Theodorescu D, Barton M. Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve? Life Sci 2012; 91:528-39. [PMID: 22967485 DOI: 10.1016/j.lfs.2012.07.034] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 07/20/2012] [Accepted: 07/24/2012] [Indexed: 02/07/2023]
Abstract
In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.
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Affiliation(s)
- Donald E Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA
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Leask A. Getting out of a sticky situation: targeting the myofibroblast in scleroderma. Open Rheumatol J 2012; 6:163-9. [PMID: 22802915 PMCID: PMC3396281 DOI: 10.2174/1874312901206010163] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2012] [Revised: 03/27/2012] [Accepted: 04/04/2012] [Indexed: 02/07/2023] Open
Abstract
There is no treatment for the fibrosis observed in scleroderma (systemic sclerosis, SSc). Although genome-wide expression profiling has suggested that differences in gene expression patters between non-lesional and lesional skin are minimal, phenotypically these areas of tissue are quite different. In fact, lesional areas of scleroderma patients can be distinguished by the presence of a differentiated form of fibroblast, termed the myofibroblast. This cell type expresses the highly contractile protein α-smooth muscle actin (α-SMA). Fibroblasts isolated from SSc lesions excessively synthesize, adhere to and contract extracellular matrix (ECM) and display activated adhesive signaling pathways. Strategies aimed at blocking myofibroblast differentiation, persistence and activity are therefore likely to be useful in alleviating the fibrosis in scleroderma.
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Affiliation(s)
- Andrew Leask
- Departments of Dentistry and Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, London, ON, N6A 5C1, Canada
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Endothelin system in intestinal villi: A possible role of endothelin-2/vasoactive intestinal contractor in the maintenance of intestinal architecture. Biochem Biophys Res Commun 2012; 417:1113-8. [DOI: 10.1016/j.bbrc.2011.12.053] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 12/14/2011] [Indexed: 02/07/2023]
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