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Increased Platelet Binding to Circulating Monocytes in Idiopathic Pulmonary Fibrosis

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Abstract

Purpose

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and its prognosis is poor. Epidemiological evidence suggests an association of IPF with vascular disease and thrombotic tendency, which may be related to platelet activation.

Methods

Platelet–monocyte adhesion in peripheral blood was examined by flow cytometry in patients with IPF (n = 19), interstitial lung disease (ILD) other than IPF (n = 9), and control subjects without pulmonary fibrosis (n = 14). Expression of platelet activation markers P-selectin (CD62P), PSGL-1 (CD162), and CD40 ligand (CD40L) on leukocytes and platelets were studied. Plasma concentrations of soluble P-selectin and CD40L were measured by ELISA.

Results

Significantly elevated levels of platelet–monocyte binding were found in patients with IPF (35.6 ± 4.34 % [mean ± SEM]) compared with patients with non-IPF ILD (23.5 ± 3.68 %) and non-ILD control subjects (16.5 ± 2.26 %; P < 0.01). There was a trend towards increased divalent cation-independent platelet–monocyte binding in IPF (6.0 ± 0.77 % [mean ± SEM]) compared with non-IPF ILD (4.3 ± 1.38 %) and control subjects without ILD (3.1 ± 1.75 %; P = 0.058). There was no differential surface expression of platelet activation markers on subsets of leukocytes or platelets. Plasma concentrations of CD40L and soluble P-selectin did not differ between IPF and control subjects. Platelet–monocyte binding had no significant correlation with percent predicted TLco or FVC.

Conclusions

Platelet–monocyte binding is increased in IPF, suggesting increased platelet activation. This conjugation is predominantly calcium-dependent, but there may be more calcium-independent adhesion in IPF. These findings support further research into the role of platelet activation in IPF.

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Abbreviations

CD40L:

CD40 ligand

FACS:

Fluorescent activated cell sorting

IPF:

Idiopathic pulmonary fibrosis

ILD:

Interstitial lung disease

mAb:

Monoclonal antibodies

PMN:

Polymorphonuclear leukocytes

References

  1. American Thoracic Society, European Respiratory Society (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 165:277–304

    Article  Google Scholar 

  2. Kim DS, Collard HR, King TE Jr (2006) Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 3:285–292

    Article  PubMed Central  PubMed  Google Scholar 

  3. Hubbard RB, Smith C, Le JI, Gribbin J, Fogarty AW (2008) The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med 178:1257–1261

    Article  PubMed  Google Scholar 

  4. Daniels CE, Yi ES, Ryu JH (2008) Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis. Eur Respir J 32:170–174

    Article  CAS  PubMed  Google Scholar 

  5. Parra ER, David YR, da Costa LR et al (2005) Heterogeneous remodeling of lung vessels in idiopathic pulmonary fibrosis. Lung 183:291–300

    Article  PubMed  Google Scholar 

  6. Ebina M, Shimizukawa M, Shibata N et al (2004) Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 169:1203–1208

    Article  PubMed  Google Scholar 

  7. Colombat M, Mal H, Groussard O et al (2007) Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics. Hum Pathol 38:60–65

    Article  CAS  PubMed  Google Scholar 

  8. Dees C, Akhmetshina A, Zerr P et al (2011) Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 208(5):961–972

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Antoniades HN, Bravo MA, Avila RE et al (1990) Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 86:1055–1064

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Bitterman PB, Adelberg S, Crystal RG (1983) Mechanisms of pulmonary fibrosis. Spontaneous release of the alveolar macrophage-derived growth factor in the interstitial lung disorders. J Clin Invest 72:1801–1813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Bitterman PB, Rennard SI, Adelberg S, Crystal RG (1983) Role of fibronectin as a growth factor for fibroblasts. J Cell Biol 97:1925–1932

    Article  CAS  PubMed  Google Scholar 

  12. Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15:255–273

    Article  CAS  PubMed  Google Scholar 

  13. Scotton CJ, Chambers RC (2007) Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest 132:1311–1321

    Article  PubMed  Google Scholar 

  14. Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494

    Article  CAS  PubMed  Google Scholar 

  15. Neumann FJ, Marx N, Gawaz M et al (1997) Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 95:2387–2394

    Article  CAS  PubMed  Google Scholar 

  16. Theilmeier G, Lenaerts T, Remacle C, Collen D, Vermylen J, Hoylaerts MF (1999) Circulating activated platelets assist THP-1 monocytoid/endothelial cell interaction under shear stress. Blood 94:2725–2734

    CAS  PubMed  Google Scholar 

  17. Merhi Y, Provost P, Guidoin R, Latour JG (1997) Importance of platelets in neutrophil adhesion and vasoconstriction after deep carotid arterial injury by angioplasty in pigs. Arterioscler Thromb Vasc Biol 17:1185–1191

    Article  CAS  PubMed  Google Scholar 

  18. Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I (2002) Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 105:2166–2171

    Article  PubMed  Google Scholar 

  19. Maclay JD, McAllister DA, Johnston S et al (2011) Increased platelet activation in patients with stable and acute exacerbation of COPD. Thorax 66:769–774

    Article  PubMed  Google Scholar 

  20. American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646–664 [Review] [234 refs]

    Article  Google Scholar 

  21. Bournazos S, Rennie J, Hart SP, Dransfield I (2008) Choice of anticoagulant critically affects measurement of circulating platelet–leukocyte complexes. Arterioscler Thromb Vasc Biol 28:e2–e3

    Article  CAS  PubMed  Google Scholar 

  22. Frenette PS, Denis CV, Weiss L et al (2000) P-selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet–endothelial interactions in vivo. J Exp Med 191:1413–1422

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Armitage RJ, Fanslow WC, Strockbine L et al (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357:80–82

    Article  CAS  PubMed  Google Scholar 

  24. Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A (1992) A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci USA 89:6550–6554

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Grammer AC, Bergman MC, Miura Y, Fujita K, Davis LS, Lipsky PE (1995) The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol 154:4996–5010

    CAS  PubMed  Google Scholar 

  26. Pinchuk LM, Klaus SJ, Magaletti DM, Pinchuk GV, Norsen JP, Clark EA (1996) Functional CD40 ligand expressed by human blood dendritic cells is up-regulated by CD40 ligation. J Immunol 157:4363–4370

    CAS  PubMed  Google Scholar 

  27. Henn V, Slupsky JR, Grafe M et al (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594

    Article  CAS  PubMed  Google Scholar 

  28. Kaufman J, Sime PJ, Phipps RP (2004) Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-gamma and IL-13, and implications for fibrosis. J Immunol 172:1862–1871

    Article  CAS  PubMed  Google Scholar 

  29. Juul K, Tybjaerg-Hansen A, Mortensen J, Lange P, Vestbo J, Nordestgaard BG (2005) Factor V leiden homozygosity, dyspnea, and reduced pulmonary function. Arch Intern Med 165:2032–2036

    Article  CAS  PubMed  Google Scholar 

  30. Chambers RC, Laurent GJ (2002) Coagulation cascade proteases and tissue fibrosis. Biochem Soc Trans 30:194–200

    Article  CAS  PubMed  Google Scholar 

  31. Howell DC, Laurent GJ, Chambers RC (2002) Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. Biochem Soc Trans 30:211–216

    Article  CAS  PubMed  Google Scholar 

  32. Howell DC, Johns RH, Lasky JA et al (2005) Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol 166:1353–1365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Magro CM, Allen J, Pope-Harman A et al (2003) The role of microvascular injury in the evolution of idiopathic pulmonary fibrosis. Am J Clin Pathol 119:556–567

    Article  PubMed  Google Scholar 

  34. Bargagli E, Madioni C, Bianchi N, Refini RM, Cappelli R, Rottoli P (2013) Serum analysis of coagulation factors in IPF and NSIP. Inflammation. doi:10.1007/s10753-013-9706-z

  35. Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI (2001) Circulating monocyte–platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 104:1533–1537

    Article  CAS  PubMed  Google Scholar 

  36. Cicha I, Garlichs CD, Daniel WG, Goppelt-Struebe M (2004) Activated human platelets release connective tissue growth factor. Thromb Haemost 91:755–760

    CAS  PubMed  Google Scholar 

  37. McKeown S, Richter AG, O’Kane C, McAuley DF, Thickett DR (2009) MMP expression and abnormal lung permeability are important determinants of outcome in IPF. Eur Respir J 33:77–84

    Article  CAS  PubMed  Google Scholar 

  38. Katsuda S, Kaji T (2003) Atherosclerosis and extracellular matrix. J Atheroscler Thromb 10:267–274

    Article  CAS  PubMed  Google Scholar 

  39. Schwartz SM, Virmani R, Rosenfeld ME (2000) The good smooth muscle cells in atherosclerosis. Curr Atheroscler Rep 2:422–429

    Article  CAS  PubMed  Google Scholar 

  40. Consigny PM (1995) Pathogenesis of atherosclerosis. AJR Am J Roentgenol 164:553–558

    Article  CAS  PubMed  Google Scholar 

  41. da Costa Martins P, van den Berk N, Ulfman LH, Koenderman L, Hordijk PL, Zwaginga JJ (2004) Platelet–monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation. Arterioscler Thromb Vasc Biol 24:193–199

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. L. Sadofsky, Mr. C. Crow, Dr. V. Green, Dr. L. Madden, and Mr. W. Sheedy for their assistance in conducting the experiments during this study. We also acknowledge Dr. V. Allgar for her help with the statistical analyses. The study was funded by the University of Hull.

Conflict of interest

None declared for any of the authors.

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Authors and Affiliations

  1. Division of Cardiovascular and Respiratory Studies, Castle Hill Hospital, Castle Road, Cottingham, HU16 5JQ, UK

    Ahmed Fahim, Michael G. Crooks, Alyn H. Morice & Simon P. Hart

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  1. Ahmed Fahim
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  2. Michael G. Crooks
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  3. Alyn H. Morice
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  4. Simon P. Hart
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Correspondence to Ahmed Fahim.

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Fahim, A., Crooks, M.G., Morice, A.H. et al. Increased Platelet Binding to Circulating Monocytes in Idiopathic Pulmonary Fibrosis. Lung 192, 277–284 (2014). https://doi.org/10.1007/s00408-013-9546-5

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  • DOI: https://doi.org/10.1007/s00408-013-9546-5

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