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. 2004 Jul;59(7):581–585. doi: 10.1136/thx.2003.009860

Angiogenic cytokines in patients with idiopathic interstitial pneumonia

N Simler 1, P Brenchley 1, A Horrocks 1, S Greaves 1, P Hasleton 1, J Egan 1
PMCID: PMC1747058  PMID: 15223865

Abstract

Background: Angiogenesis has been implicated in the pathogenesis of idiopathic interstitial pneumonia (IIP). The aim of this study was to examine the relationship between plasma concentrations of the angiogenic cytokines interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) and clinical parameters of disease progression over a 6 month period to identify potential aetiological mediators and prognostic markers of disease activity in patients with IIP.

Methods: Forty nine patients with IIP (40 men) were recruited to the study. Plasma cytokine measurements, pulmonary function tests, and high resolution computed tomography (HRCT) scans were performed on recruitment and after 6 months. Plasma cytokine measurements were also performed in 15 healthy volunteers for control purposes.

Results: Patients with IIP had significantly higher median (IQR) baseline concentrations of IL-8 and ET-1 than controls (155 (77–303) pg/ml v 31 (0–100) pg/ml, p<0.001) and (1.21 (0.91–1.88) pg/ml v 0.84 (0.67–1.13) pg/ml, p<0.01), respectively. Baseline concentrations of IL-8, ET-1, and VEGF were significantly related to the baseline HRCT fibrosis score (r = 0.42, p<0.005; r = 0.39, p<0.01; and r = 0.42, p<0.005, respectively). Patients with IIP who developed progressive disease had significantly higher baseline levels of IL-8 (345 (270–497) pg/ml v 121 (73–266) pg/ml, p = 0.001) and VEGF (1048 (666–2149) pg/ml v 658 (438–837) pg/ml, p = 0.019). Over 6 months the change in VEGF was significantly related to the change in HRCT fibrosis score (r = 0.565, p = 0.035) and negatively related to the change in forced vital capacity (r = –0.353, p = 0.035).

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Selected References

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  1. American Thoracic Society. European Respiratory Society 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. 2002 Jan 15;165(2):277–304. doi: 10.1164/ajrccm.165.2.ats01. [DOI] [PubMed] [Google Scholar]
  2. Bjoraker J. A., Ryu J. H., Edwin M. K., Myers J. L., Tazelaar H. D., Schroeder D. R., Offord K. P. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998 Jan;157(1):199–203. doi: 10.1164/ajrccm.157.1.9704130. [DOI] [PubMed] [Google Scholar]
  3. Egan J. J., Hasleton P. S. Cryptogenic fibrosing alveolitis: diagnosis and treatment. Hosp Med. 1998 May;59(5):364–368. [PubMed] [Google Scholar]
  4. Fagan K. A., McMurtry I. F., Rodman D. M. Role of endothelin-1 in lung disease. Respir Res. 2001 Feb 22;2(2):90–101. doi: 10.1186/rr44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fehrenbach H., Haase M., Kasper M., Koslowski R., Schuh D., Müller M. Alterations in the immunohistochemical distribution patterns of vascular endothelial growth factor receptors Flk1 and Flt1 in bleomycin-induced rat lung fibrosis. Virchows Arch. 1999 Jul;435(1):20–31. doi: 10.1007/s004280050390. [DOI] [PubMed] [Google Scholar]
  6. Fehrenbach H., Kasper M., Haase M., Schuh D., Müller M. Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: light, fluorescence, and electron microscopy. Anat Rec. 1999 Jan;254(1):61–73. doi: 10.1002/(SICI)1097-0185(19990101)254:1<61::AID-AR8>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  7. Flaherty K. R., Thwaite E. L., Kazerooni E. A., Gross B. H., Toews G. B., Colby T. V., Travis W. D., Mumford J. A., Murray S., Flint A. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003 Feb;58(2):143–148. doi: 10.1136/thorax.58.2.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Flaherty K. R., Travis W. D., Colby T. V., Toews G. B., Kazerooni E. A., Gross B. H., Jain A., Strawderman R. L., Flint A., Lynch J. P. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001 Nov 1;164(9):1722–1727. doi: 10.1164/ajrccm.164.9.2103074. [DOI] [PubMed] [Google Scholar]
  9. Gay S. E., Kazerooni E. A., Toews G. B., Lynch J. P., 3rd, Gross B. H., Cascade P. N., Spizarny D. L., Flint A., Schork M. A., Whyte R. I. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1063–1072. doi: 10.1164/ajrccm.157.4.9703022. [DOI] [PubMed] [Google Scholar]
  10. Giaid A., Michel R. P., Stewart D. J., Sheppard M., Corrin B., Hamid Q. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet. 1993 Jun 19;341(8860):1550–1554. doi: 10.1016/0140-6736(93)90694-c. [DOI] [PubMed] [Google Scholar]
  11. Hanley J. A., McNeil B. J. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982 Apr;143(1):29–36. doi: 10.1148/radiology.143.1.7063747. [DOI] [PubMed] [Google Scholar]
  12. Hocher B., Schwarz A., Fagan K. A., Thöne-Reineke C., El-Hag K., Kusserow H., Elitok S., Bauer C., Neumayer H. H., Rodman D. M. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol. 2000 Jul;23(1):19–26. doi: 10.1165/ajrcmb.23.1.4030. [DOI] [PubMed] [Google Scholar]
  13. Katzenstein Anna-Luise A., Zisman David A., Litzky Leslie A., Nguyen Binh T., Kotloff Robert M. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol. 2002 Dec;26(12):1567–1577. doi: 10.1097/00000478-200212000-00004. [DOI] [PubMed] [Google Scholar]
  14. Kazerooni E. A., Martinez F. J., Flint A., Jamadar D. A., Gross B. H., Spizarny D. L., Cascade P. N., Whyte R. I., Lynch J. P., 3rd, Toews G. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol. 1997 Oct;169(4):977–983. doi: 10.2214/ajr.169.4.9308447. [DOI] [PubMed] [Google Scholar]
  15. Keane M. P., Arenberg D. A., Lynch J. P., 3rd, Whyte R. I., Iannettoni M. D., Burdick M. D., Wilke C. A., Morris S. B., Glass M. C., DiGiovine B. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol. 1997 Aug 1;159(3):1437–1443. [PubMed] [Google Scholar]
  16. Keane M. P., Belperio J. A., Arenberg D. A., Burdick M. D., Xu Z. J., Xue Y. Y., Strieter R. M. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999 Nov 15;163(10):5686–5692. [PubMed] [Google Scholar]
  17. Keane M. P., Belperio J. A., Burdick M. D., Lynch J. P., Fishbein M. C., Strieter R. M. ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001 Dec 15;164(12):2239–2242. doi: 10.1164/ajrccm.164.12.2104106. [DOI] [PubMed] [Google Scholar]
  18. Keane Michael P., Strieter Robert M. The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease. Respir Res. 2001 Oct 15;3:5–5. doi: 10.1186/rr177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kikuchi K., Kubo M., Kadono T., Yazawa N., IHN H., Tamaki K. Serum concentrations of vascular endothelial growth factor in collagen diseases. Br J Dermatol. 1998 Dec;139(6):1049–1051. doi: 10.1046/j.1365-2133.1998.02563.x. [DOI] [PubMed] [Google Scholar]
  20. Koyama Sekiya, Sato Etsuro, Haniuda Masayuki, Numanami Hiroki, Nagai Sonoko, Izumi Takateru. Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Am J Respir Crit Care Med. 2002 Aug 1;166(3):382–385. doi: 10.1164/rccm.2103112. [DOI] [PubMed] [Google Scholar]
  21. Meyer K. C., Cardoni A., Xiang Z. Z. Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects and patients with diffuse parenchymal lung disease. J Lab Clin Med. 2000 Apr;135(4):332–338. doi: 10.1067/mlc.2000.105618. [DOI] [PubMed] [Google Scholar]
  22. Michael J. R., Markewitz B. A. Endothelins and the lung. Am J Respir Crit Care Med. 1996 Sep;154(3 Pt 1):555–581. doi: 10.1164/ajrccm.154.3.8810589. [DOI] [PubMed] [Google Scholar]
  23. Monacci W. T., Merrill M. J., Oldfield E. H. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol. 1993 Apr;264(4 Pt 1):C995–1002. doi: 10.1152/ajpcell.1993.264.4.C995. [DOI] [PubMed] [Google Scholar]
  24. Mutsaers S. E., Marshall R. P., Goldsack N. R., Laurent G. J., McAnulty R. J. Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Pulm Pharmacol Ther. 1998 Apr-Jun;11(2-3):221–225. doi: 10.1006/pupt.1998.0142. [DOI] [PubMed] [Google Scholar]
  25. Peão M. N., Aguas A. P., de Sá C. M., Grande N. R. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat Rec. 1994 Jan;238(1):57–67. doi: 10.1002/ar.1092380108. [DOI] [PubMed] [Google Scholar]
  26. TURNER-WARWICK M. PRECAPILLARY SYSTEMIC-PULMONARY ANASTOMOSES. Thorax. 1963 Sep;18:225–237. doi: 10.1136/thx.18.3.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Veikkola T., Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol. 1999 Jun;9(3):211–220. doi: 10.1006/scbi.1998.0091. [DOI] [PubMed] [Google Scholar]

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