Current Rheumatology Reports

, 15:381 | Cite as

Scleroderma-Related Lung Disease: Are Adipokines Involved Pathogenically?

  • Shannon Haley
  • Dilip Shah
  • Freddy Romero
  • Ross Summer
SCLERODERMA (J VARGA, SECTION EDITOR)
Part of the following topical collections:
  1. Topical Collection on Scleroderma

Abstract

Scleroderma is a systemic autoimmune disease of unknown etiology whose characteristic features include endothelial cell dysfunction, fibroblast proliferation, and immune dysregulation. Although almost any organ can be pathologically involved in scleroderma, lung complications including interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading cause of death in patients with this condition. Currently, the molecular mechanisms leading to development of scleroderma-related lung disease are poorly understood; however, the systemic nature of this condition has led many to implicate circulating factors in the pathogenesis of some of its organ impairment. In this article we focus on a new class of circulating factors derived from adipose-tissue called adipokines, which are known to be altered in scleroderma. Recently, the adipokines adiponectin and leptin have been found to regulate biological activity in endothelial, fibroblast, and immune cell types in lung and in many other tissues. The pleiotropic nature of these circulating factors and their functional activity on many cell types implicated in the pathogenesis of ILD and PAH suggest these hormones may be mechanistically involved in the onset and/or progression of scleroderma-related lung diseases.

Keywords

Scleroderma Adipokines Adiponectin Leptin Interstitial lung disease Pulmonary fibrosis Pulmonary hypertension 

Notes

Acknowledgment

This work was supported by National Institutes of Health (NIH) grant no. R01HL105490.

Compliance with Ethics Guidelines

Conflict of Interest

Shannon Haley, Dilip Shah, Freddy Romero, and Ross Summer declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66:940–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Wells AU, Steen V, Valentini G. Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology (Oxford, England). 2009;48 Suppl 3:iii40–4.Google Scholar
  3. 3.
    Leibel RL, Bahary N, Friedman JM. Genetic variation and nutrition in obesity: approaches to the molecular genetics of obesity. World Rev Nutr Diet. 1990;63:90–101.PubMedGoogle Scholar
  4. 4.
    Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S. Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem Biophys Res Commun. 2009;384:311–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Frühbeck G. Intracellular signalling pathways activated by leptin. Biochem J. 2006;393:7–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Kim GS, Hong JS, Kim SW, Koh J-M, An CS, Choi J-Y, et al. Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. J Biol Chem. 2003;278:21920–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Dreyer MG, Juge-Aubry CE, Gabay C, Lang U, Rohner-Jeanrenaud F, Dayer J-M, et al. Leptin activates the promoter of the interleukin-1 receptor antagonist through p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa B/PU.1 binding site. Biochem J. 2003;370:591–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Tomizawa A, Hattori Y, Kasai K, Nakano Y. Adiponectin induces NF-kappaB activation that leads to suppression of cytokine-induced NF-kappaB activation in vascular endothelial cells: globular adiponectin vs. high molecular weight adiponectin. Diabetes Vasc Dis Res Off J Int Soc Diabetes Vasc Disease Soc Diabetes Vasc Dis. 2008;5:123–7.CrossRefGoogle Scholar
  9. 9.
    •• Pehlivan Y, Onat AM, Ceylan N, Turkbeyler IH, Buyukhatipoglu H, Comez G, et al. Serum leptin, resistin and TNF-α levels in patients with systemic sclerosis: the role of adipokines in scleroderma. Int J Rheum Dis. 2012;15:374–9. This study was one of the first to investigate the relationship between circulating adipokines and scleroderma.PubMedCrossRefGoogle Scholar
  10. 10.
    Karmiris K, Koutroubakis IE, Xidakis C, Polychronaki M, Voudouri T, Kouroumalis EA. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Inflamm Bowel Dis. 2006;12:100–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Kotulska A, Kucharz EJ, Brzezińska-Wcisło L, Wadas U. A decreased serum leptin level in patients with systemic sclerosis. Clin Rheumatol. 2001;20:300–2.PubMedCrossRefGoogle Scholar
  12. 12.
    Summer R, Fiack CA, Ikeda Y, Sato K, Dwyer D, Ouchi N, et al. Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease. Am J Physiol Lung Cell Mol Physiol. 2009;297:L432–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen H, Zhang J-P, Huang H, Wang Z-H, Cheng R, Cai W-B. Leptin promotes fetal lung maturity and upregulates SP-A expression in pulmonary alveoli type-II epithelial cells involving TTF-1 activation. PloS One. 2013;8:e69297.PubMedCrossRefGoogle Scholar
  14. 14.
    Vernooy JHJ, Ubags NDJ, Brusselle GG, Tavernier J, Suratt BT, Joos GF, et al. Leptin as regulator of pulmonary immune responses: involvement in respiratory diseases. Pulm Pharmacol Ther. 2013;26:464–72.PubMedCrossRefGoogle Scholar
  15. 15.
    Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol. 2009;175:3–16.PubMedCrossRefGoogle Scholar
  16. 16.
    • Hassoun PM. Lung involvement in systemic sclerosis. Presse Méd (Paris, France: 1983). 2011;40:e3–e17. This review is a comprehensive overview of scleroderma-associated ILD and PAH.CrossRefGoogle Scholar
  17. 17.
    Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S20–31.PubMedCrossRefGoogle Scholar
  18. 18.
    • Mathai SC, Hassoun PM. Pulmonary arterial hypertension in connective tissue diseases. Heart Fail Clin. 2012;8:413–25. This is a good review of pulmonary arterial hypertension in connective tissue disease.PubMedCrossRefGoogle Scholar
  19. 19.
    Benan M, Hande I, Gul O. The natural course of progressive systemic sclerosis patients with interstitial lung involvement. Clin Rheumatol. 2007;26:349–54.PubMedCrossRefGoogle Scholar
  20. 20.
    Cappelli S, Guiducci S, Bellando Randone S, Matucci Cerinic M. Immunosuppression for interstitial lung disease in systemic sclerosis. Eur Respir Rev. 2013;22:236–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Coghlan JG, Mukerjee D. The heart and pulmonary vasculature in scleroderma: clinical features and pathobiology. Curr Opin Rheumatol. 2001;13:495–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuka ME, et al. Survival and predictors of mortality in systemic sclerosis associated pulmonary arterial hypertension: outcomes from the PHAROS registry. Arthritis Care Res. 2013. doi: 10.1002/acr.22121.
  23. 23.
    Le Pavec J, Humbert M, Mouthon L, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;181:1285–93.PubMedCrossRefGoogle Scholar
  24. 24.
    Lefèvre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M, et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum. 2013. doi: 10.1002/art.38029.
  25. 25.
    Rubin R, Strayer DS. Interstitial lung disease; pulmonary hypertension. In: Rubin E, editor. Rubin’s pathology clinicopathologic foundations of medicine, 5th Ed., Lippincott Williams & Wilkins; 2008, p. 524–34;536–538.Google Scholar
  26. 26.
    Combs TP, Wagner JA, Berger J, Doebber T, Wang W-J, Zhang BB, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology. 2002;143:998–1007.PubMedCrossRefGoogle Scholar
  27. 27.
    Addabbo F, Nacci C, De Benedictis L, Leo V, Tarquinio M, Quon MJ, et al. Globular adiponectin counteracts VCAM-1-mediated monocyte adhesion via AdipoR1/NF-κB/COX-2 signaling in human aortic endothelial cells. Am J Physiol Endocrinol Metab. 2011;301:E1143–54.PubMedCrossRefGoogle Scholar
  28. 28.
    Medoff BD, Okamoto Y, Leyton P, Weng M, Sandall BP, Raher MJ, et al. Adiponectin deficiency increases allergic airway inflammation and pulmonary vascular remodeling. Am J Respir Cell Mol Biol. 2009;41:397–406.PubMedCrossRefGoogle Scholar
  29. 29.
    •• Weng M, Raher MJ, Leyton P, Combs TP, Scherer PE, Bloch KD, et al. Adiponectin decreases pulmonary arterial remodeling in murine models of pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45:340–7. This study was the second to demonstrate the importance of adiponectin in lung vascular remodeling.PubMedCrossRefGoogle Scholar
  30. 30.
    Schraw T, Wang ZV, Halberg N, Hawkins M, Scherer PE. Plasma adiponectin complexes have distinct biochemical characteristics. Endocrinology. 2008;149:2270–82.PubMedCrossRefGoogle Scholar
  31. 31.
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Pischon T. Adiponectin: stability in plasma over 36 hours and within-person variation over 1 year. Clin Chem. 2003;49:650–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab. 2003;285:E527–33.PubMedGoogle Scholar
  34. 34.
    Matsuda M, Shimomura I. Roles of adiponectin and oxidative stress in obesity-associated metabolic and cardiovascular diseases. Rev Endocr Metab Disord. 2013. doi: 10.1007/s11154-013-9271-7.
  35. 35.
    Masui Y, Asano Y, Takahashi T, Shibata S, Akamata K, Aozasa N, et al. Clinical significance of monitoring serum adiponectin levels during intravenous pulse cyclophosphamide therapy in interstitial lung disease associated with systemic sclerosis. Mod Rheumatol Jpn Rheum Assoc. 2013;23:323–9.CrossRefGoogle Scholar
  36. 36.
    Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol. 2008;121:326–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Sam F, Walsh K. What can adiponectin say about left ventricular function? Heart. 2010;96:331–2.PubMedCrossRefGoogle Scholar
  38. 38.
    • Williams AS, Kasahara DI, Verbout NG, Fedulov AV, Zhu M, Si H, et al. Role of the adiponectin binding protein, T-cadherin (Cdh13), in allergic airways responses in mice. PloS One. 2012;7:e41088. This study illustrates the importance of T-cadherin in facilitating the mobilization of adiponectin into the lung.PubMedCrossRefGoogle Scholar
  39. 39.
    Denzel MS, Scimia M-C, Zumstein PM, Walsh K, Ruiz-Lozano P, Ranscht B. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest. 2010;120:4342–52.PubMedCrossRefGoogle Scholar
  40. 40.
    Miller M, Cho JY, Pham A, Ramsdell J, Broide DH. Adiponectin and functional adiponectin receptor 1 are expressed by airway epithelial cells in chronic obstructive pulmonary disease. J Immunol (Baltimore, Md: 1950). 2009;182:684–91.Google Scholar
  41. 41.
    Summer R, Little FF, Ouchi N, Takemura Y, Aprahamian T, Dwyer D, et al. Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1035–42.PubMedCrossRefGoogle Scholar
  42. 42.
    Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation. 2002;105:2893–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, et al. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem. 2002;277:37487–91.PubMedCrossRefGoogle Scholar
  44. 44.
    Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84:767–801.PubMedCrossRefGoogle Scholar
  45. 45.
    Ding M, Xie Y, Wagner RJ, Jin Y, Carrao AC, Liu LS, et al. Adiponectin induces vascular smooth muscle cell differentiation via repression of mammalian target of rapamycin complex 1 and FoxO4. Arterioscler Thromb Vasc Biol. 2011;31:1403–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Wang W, Zhao C, Wang Y, He X, Shen C, Cao W, et al. Adiponectin inhibits the activation of hepatic stellate cells induced by TGFb1 via up-regulating the expression of eNOS. Zhonghua Gan Zang Bing Za Zhi = Zhonghua Ganzangbing Zazhi = Chin J Hepatol. 2011;19:917–22.Google Scholar
  47. 47.
    Masui Y, Asano Y, Shibata S, Noda S, Aozasa N, Akamata K, et al. Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis. J Eur Acad Dermatol Venereol JEADV. 2012;26:354–60.CrossRefGoogle Scholar
  48. 48.
    •• Fang F, Liu L, Yang Y, Tamaki Z, Wei J, Marangoni RG, et al. The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy. Arthritis Res Ther. 2012;14:R229. This study, the first to demonstrate the anti-fibrotic effects of adiponectin in normal and scleroderma fibroblasts, elucidated signaling pathways important for this effect.PubMedCrossRefGoogle Scholar
  49. 49.
    Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, et al. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes. 1996;45:1511–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Prolo P, Wong ML, Licinio J. Leptin. Int J Biochem Cell Biol. 1998;30:1285–90.PubMedCrossRefGoogle Scholar
  51. 51.
    Madej T, Boguski MS, Bryant SH. Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett. 1995;373:13–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998;12:57–65.PubMedGoogle Scholar
  53. 53.
    •• Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;40:895–904. This study was one of the first to show that serum levels of leptin are increased in patients with scleroderma-associated PAH, compared with controls.PubMedCrossRefGoogle Scholar
  54. 54.
    Biesiada G, Czepiel J, Ptak-Belowska A, Targosz A, Krzysiek-Maczka G, Strzalka M, et al. Expression and release of leptin and proinflammatory cytokines in patients with ulcerative colitis and infectious diarrhea. J Physiol Pharmacol Off J Pol Physiol Soc. 2012;63:471–81.Google Scholar
  55. 55.
    Muoio DM, Lynis Dohm G. Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab. 2002;16:653–66.PubMedCrossRefGoogle Scholar
  56. 56.
    Bjørbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res. 2004;59:305–31.PubMedCrossRefGoogle Scholar
  57. 57.
    Hegyi K, Fülöp K, Kovács K, Tóth S, Falus A. Leptin-induced signal transduction pathways. Cell Biol Int. 2004;28:159–69.PubMedCrossRefGoogle Scholar
  58. 58.
    •• Jain M, Budinger GRS, Lo A, Urich D, Rivera SE, Ghosh AK, et al. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferator-activated receptor-γ. Am J Respir Crit Care Med. 2011;183:1490–8. This was the first study to demonstrate that leptin promotes the development of bleomycin-induced lung fibrosis in mice by augmentation of TGF-β signaling.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhou Y, Jia X, Qin J, Lu C, Zhu H, Li X, et al. Leptin inhibits PPARgamma gene expression in hepatic stellate cells in the mouse model of liver damage. Mol Cell Endocrinol. 2010;323:193–200.PubMedCrossRefGoogle Scholar
  60. 60.
    Hoda MR, Keely SJ, Bertelsen LS, Junger WG, Dharmasena D, Barrett KE. Leptin acts as a mitogenic and antiapoptotic factor for colonic cancer cells. Br J Surg. 2007;94:346–54.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shannon Haley
    • 1
  • Dilip Shah
    • 1
  • Freddy Romero
    • 1
  • Ross Summer
    • 1
  1. 1.Center for Translational MedicineThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations