Skip to main content

Advertisement

SpringerLink
Log in

The antifibrotic effects of alveolar macrophages 5-HT2C receptors blockade on bleomycin-induced pulmonary fibrosis in rats

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

The most widespread chronic fibrosing lung disease is idiopathic pulmonary fibrosis. Lung serotonin (5-HT) content is increased during pulmonary fibrosis with the implication of 5-HT2 receptors in the pathogenesis. Serotonin plays important roles in alveolar macrophages function through 5-HT2C receptors activation. Numerous studies described the important role of 5-HT2A/B receptor blockers in suppressing different types of fibrosis as idiopathic pulmonary fibrosis. The current study pointed to examine the antifibrotic effects of RS-102221 and/or terguride through in vivo model of pulmonary fibrosis.

Methods

Induction of pulmonary fibrosis was through a single dose of intra-tracheal bleomycin instillation (5 mg/kg dissolved in phosphate buffer saline) in adult male albino Wistar rats. Next day of bleomycin instillation, intraperitoneal injection of RS-102221 (0.5 mg/kg/d) and/or terguride (1.2 mg/kg/d) were administered and continued for 14 days.

Results

Noticeable increase in 5-HT2C receptors expression was observed in fibrotic lung tissues with marked allocation belonging to alveolar macrophages. Either RS-102221 or terguride reduced the increments in lung water contents, grading of lung fibrosis, lung tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1) and vascular endothelial growth factor (VEGF) levels in lung injury and fibrosis-induced by bleomycin. Moreover, collagen content and myofibroblasts-alpha smooth muscle actin (α − SМA) were significantly decreased. Additionally, the simultaneous administration of RS-102221 with terguride had a synergistic outcome compared to that obtained by individual monotherapy.

Conclusion

These findings suggested the potential use of 5-HT2A/B/C antagonists as anti-fibrotic agents in lung fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

α-SMA:

Alpha-smooth muscle actin

ELISA:

Enzyme linked immunoassay

PBS:

Phosphate buffered saline

5-HT:

Serotonin

TGF-β1:

Transforming growth factor-beta1

TNF-α:

Tumor necrosis factor-alpha

VEGF:

Vascular endothelial growth factor

References

  1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824, doi:https://doi.org/10.1164/rccm.2009-040GL

    Article  Google Scholar 

  2. Boorsma CE, Draijer C, Melgert BN. Macrophage heterogeneity in respiratory diseases. Mediators Inflamm 2013;2013:1–19, doi:https://doi.org/10.1155/2013/769214.

    Article  Google Scholar 

  3. Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 2012;380:680–8, doi:https://doi.org/10.1016/S0140-6736(12)61144-1.

    Article  CAS  Google Scholar 

  4. Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C, Horowitz D, et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;185:67–76, doi:https://doi.org/10.1164/rccm.201101-0058OC.

    Article  CAS  Google Scholar 

  5. Luo F, Zhuang Y, Sides MD, Sanchez CG, Shan B, White ES, et al. Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo. Respir Res 2014;15:51, doi:https://doi.org/10.1186/1465-9921-15-51.

    Google Scholar 

  6. Samah M, El-Aidy AE-R, Tawfik MK, Ewais MMS. Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats. Eur J Pharmacol 2012;689:186–93, doi:https://doi.org/10.1016/j.ejphar.2012.05.026.

    Article  CAS  Google Scholar 

  7. Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–76, doi:https://doi.org/10.1038/nm0603-669.

    Article  CAS  Google Scholar 

  8. Fabre A, Marchal-Somme J, Marchand-Adam S, Quesnel C, Borie R, Dehoux M, et al. Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice. Eur Respir J 2008;32:426–36, doi:https://doi.org/10.1183/09031936.00126907.

    Article  CAS  Google Scholar 

  9. Mann DA, Oakley F. Serotonin paracrine signaling in tissue fibrosis. Biochim Biophys Acta 2013;1832:905–10, doi:https://doi.org/10.1016/j.bbadis.2012.09.009.

    Article  CAS  Google Scholar 

  10. Mikulski Z, Zaslona Z, Cakarova L, Hartmann P, Wilhelm J, Tecott LH, et al. Serotonin activates murine alveolar macrophages through 5-HT2C receptors. Am J Physiol Lung Cell Mol Physiol 2010;299:L272–280, doi:https://doi.org/10.1152/ajplung.00032.2010.

    Article  CAS  Google Scholar 

  11. Königshoff M, Dumitrascu R, Udalov S, Amarie OV, Reiter R, Grimminger F, et al. Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention. Thorax 2010;65:949–55, doi:https://doi.org/10.1136/thx.2009.134353.

    Article  Google Scholar 

  12. Dumitrascu R, Kulcke C, Königshoff M, Kouri F, Yang X, Morrell N, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur Respir J 2011;37:1104–18, doi:https://doi.org/10.1183/09031936.00126010.

    Article  CAS  Google Scholar 

  13. Steardo L, Monteleone P, Trabace L, Cannizzaro C, Maj M, Cuomo V. Serotonergic modulation of rat pineal gland activity: in vivo evidence for a 5-Hydroxytryptamine(2C) receptor involvement. J Pharmacol Exp Ther 2000;295:266–73.

    CAS  PubMed  Google Scholar 

  14. Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008;590:400–8, doi:https://doi.org/10.1016/j.ejphar.2008.06.046.

    Article  CAS  Google Scholar 

  15. Chen F, Gong L, Zhang L, Wang H, Qi X, Wu X, et al. Short courses of low dose dexamethasone delay bleomycin-induced lung fibrosis in rats. Eur J Pharmacol 2006;536:287–95, doi:https://doi.org/10.1016/j.ejphar.2006.03.011.

    Article  CAS  Google Scholar 

  16. Lee S-H, Jang A-S, Kim Y-E, Cha J-Y, Kim T-H, Jung S, et al. Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis. Respir Res 2010;11:16, doi:https://doi.org/10.1186/1465-9921-11-16.

    Article  Google Scholar 

  17. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 1988;41:467–70.

    Article  CAS  Google Scholar 

  18. Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol 1994;145:114–25.

    CAS  PubMed  Google Scholar 

  19. Welsh DJ, Harnett M, MacLean M, Peacock AJ. Proliferation and signaling in fibroblasts: role of 5-hydroxytryptamine2A receptor and transporter. Am J Respir Crit Care Med 2004; 170:252–9, doi:https://doi.org/10.1164/rccm.200302-264OC.

    Article  Google Scholar 

  20. Wang L, Tassiulas I, Park-Min K-H, Reid AC, Gil-Henn H, Schlessinger J, et al. Tuning of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol 2008;9:186–93, doi:https://doi.org/10.1038/ni1548.

    Article  CAS  Google Scholar 

  21. Wynn TA, Barron L. Macrophages master regulators of inflammation and fibrosis. Semin Liver Dis 2010;30:245–57, doi:https://doi.org/10.1055/s-0030-1255354.

    Article  CAS  Google Scholar 

  22. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med 2011;208:1339–50, doi:https://doi.org/10.1084/jem.20110551.

    Article  CAS  Google Scholar 

  23. Todd NW, Luzina IG, Atamas SP. Molecular and cellular mechanisms of pulmonary fibrosis. Fibrogenesis Tissue Repair 2012;5:11, doi:https://doi.org/10.1186/1755-1536-5-11.

    Google Scholar 

  24. Feske S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 2007;7:690–702, doi:https://doi.org/10.1038/nri2152.

    Article  CAS  Google Scholar 

  25. Lattin J, Zidar DA, Schroder K, Kellie S, Hume DA, Sweet MJ. G-protein-coupled receptor expression, function, and signaling in macrophages. J Leukoc Biol 2007;82:16–32, doi:https://doi.org/10.1189/jlb.0107051.

    Article  CAS  Google Scholar 

  26. Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, et al. RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 1997;36:621–9.

    Article  CAS  Google Scholar 

  27. Lech M, Anders H-J. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochim Biophys Acta 2013;1832:989–97, doi:https://doi.org/10.1016/j.bbadis.2012.12.001.

    Article  CAS  Google Scholar 

  28. Keane MP. The role of chemokines and cytokines in lung fibrosis. Eur Respir Rev 2008;17:151–6, doi:https://doi.org/10.1183/09059180.00010908.

    Article  Google Scholar 

  29. Sullivan DE, Ferris M, Pociask D, Brody AR. Tumor necrosis factor-alpha induces transforming growth factor-beta1 expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. Am J Respir Cell Mol Biol 2005;32:342–9, doi:https://doi.org/10.1165/rcmb.2004-0288OC.

    Article  CAS  Google Scholar 

  30. Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev 2015;24:102–14, doi:https://doi.org/10.1183/09059180.00003214.

    Article  Google Scholar 

  31. Greene EL, Houghton O, Collinsworth G, Garnovskaya MN, Nagai T, Sajjad T, et al. 5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O (2) generation in rat renal mesangial cells. Am J Physiol Renal Physiol 2000;278:F650–658.

    Article  CAS  Google Scholar 

  32. Tabata C, Tabata R, Kadokawa Y, Hisamori S, Takahashi M, Mishima M, et al. Thalidomide prevents bleomycin-induced pulmonary fibrosis in mice. J Immunol Baltim Md 1950 2007;179:708–14.

    CAS  Google Scholar 

  33. Wan Y-Y, Tian G-Y, Guo H-S, Kang Y-M, Yao Z-H, Li X-L, et al. Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats. Respir Res 2013;14:56, doi:https://doi.org/10.1186/1465-9921-14-56.

    Article  Google Scholar 

  34. Ruddell RG, Oakley F, Hussain Z, Yeung I, Bryan-Lluka LJ, Ramm GA, et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am J Pathol 2006;169:861–76, doi:https://doi.org/10.2353/ajpath.2006.050767.

    Article  CAS  Google Scholar 

  35. Dees C, Akhmetshina A, Zerr P, Reich N, Palumbo K, Horn A, et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 2011;208:961–72, doi:https://doi.org/10.1084/jem.20101629.

    Article  CAS  Google Scholar 

  36. Bayer H, Müller T, Myrtek D, Sorichter S, Ziegenhagen M, Norgauer J, et al. Serotoninergic receptors on human airway epithelial cells. Am J Respir Cell Mol Biol 2007;36:85–93, doi:https://doi.org/10.1165/rcmb.2006-0151OC.

    Article  CAS  Google Scholar 

  37. Löfdahl A, Holst MC, Thiman L, Wenglén C, Rydell-Törmänen K, Larsson Callerfelt A-K, et al. The role of 5-H receptors in the early development of lung fibrosis. Eur Respir J 2014;T2 Published 1 September 2014.

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Samah M. Elaidy & Soha S. Essawy

Authors
  1. Samah M. Elaidy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soha S. Essawy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Samah M. Elaidy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elaidy, S.M., Essawy, S.S. The antifibrotic effects of alveolar macrophages 5-HT2C receptors blockade on bleomycin-induced pulmonary fibrosis in rats. Pharmacol. Rep 68, 1244–1253 (2016). https://doi.org/10.1016/j.pharep.2016.08.005

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2016.08.005

Keywords

Search

Navigation