Skip to main content

Advertisement

SpringerLink
Log in

The Role of CXC Chemokines in Pulmonary Fibrosis of Systemic Lupus Erythematosus Patients

  • Original Article
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

The inflammatory process in systemic lupus erythematosus (SLE) affects many organs including the lungs. CXC chemokines are suggested to play an important role in the pathogenesis of SLE and pulmonary fibrosis. To estimate the concentrations of CXCL9, CXCL10, CXCL11 in bronchoalveolar lavage fluid (BALF) of patients with and without pulmonary involvements of SLE to evaluate CXC chemokines role in the pathogenesis of pulmonary fibrosis in SLE. Twenty-six SLE patients and 31 healthy controls were evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, the SLE Disease Activity Index (SLEDAI), assessing CXCL9, CXCL11, CXCL10 level in BALF (an enzyme-immunosorbent assay kit). The mean CXCL9 and CXCL11 concentrations in BALF were higher in SLE patients compared to healthy controls (34.09 ± 102.34 vs 10.98 ± 14.65 pg/mL, p < 0.001; 72.65 ± 112.89 vs 16.12 ± 83.75 pg/mL, p = 0.012, respectively). The disease activity scored by SLEDAI and the concentration of CXCL10 in BALF were significantly higher in the SLE patients with pulmonary fibrosis when compared with patients with normal HRCT (8.23 ± 3.19 vs 5.01 ± 2.41; 73.45 ± 34.12 vs 40.76 ± 41.65, respectively, in both p < 0.05). In SLE patients positive correlations were found between SLEDAI and the percentage of lymphocytes in BALF (r = 0.51, p < 0.05); CXCL9 and CXCL10 concentrations in BALF (r = 0.65, p < 0.001); CXCL9 and CXCL11 concentrations in BALF (r = 0.69, p < 0.001). In lupus patients with pulmonary manifestations positive correlations were found between CXCL11 concentration in BALF and SLEDAI (r = 0.55, p < 0.05), CXCL11 concentration and the percentage of neutrophils in BALF (r = 0.69, p < 0.05), CXCL10 concentration and the percentage of neutrophils in BALF (r = 0.57, p < 0.05). Our observations indicate that CXCL9 and CXCL11 play an important role in the pathogenesis of SLE but it needs further studies. These results suggest that CXCL10 and CXCL11 are associated with neutrophils accumulation in the alveolar space of SLE patients with pulmonary fibrosis and should be considered as potential factor of interstitial 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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abujam B, Cheekatla S, Aggarwal A (2013) Urinary CXCL-10/CXCL10 and MCP-1 as markers to assess activity of lupus nephritis. Lupus 22:614–623

    Article  CAS  PubMed  Google Scholar 

  • Abu-Shakra M, Urowitz MB, Gladman DD et al (1995) Mortality studies in systemic lupus erythematosus. Results from a single center. Causes of death. J Rheumatol 22(7):1259–1264

    CAS  PubMed  Google Scholar 

  • Antonelli A, Ferrari SM, Giuggioli D et al (2014) Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 13:272–280

    Article  CAS  PubMed  Google Scholar 

  • Antoniou KM, Tzouvelekis A, Alexandrakis MG et al (2006) Different angiogenic activity in pulmonary sarcoidosis and idiopathic pulmonary fibrosis. Chest 130:982–988

    Article  PubMed  Google Scholar 

  • Balabanian K, Couderc J, Bouchet-Delbos L et al (2003) Role of the chemokine stromal cell-derived factor 1 in autoantibody production and nephritis in murine lupus. J Immunol 170:3392–3400

    Article  CAS  PubMed  Google Scholar 

  • Bauer JW, Petri M, Batliwalla FM et al (2009) Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum 60:3098–3107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Belperio JA, Keane MP, Arenberg DA et al (2000) CXC chemokines in angiogenesis. J Leukoc Biol 68:1–8

    CAS  PubMed  Google Scholar 

  • Bombardier C, Gladman DD, Urowitz MB et al (1992) Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum 35:630–664

    Article  CAS  PubMed  Google Scholar 

  • British Thoracic Society Bronchoscopy Guidelines Committee, a Subcommittee of the Standards of Care Committee of the British Thoracic Society (2001) British Thoracic Society guidelines on diagnostic flexible bronchoscopy. Thorax 56(suppl 1):i1–i21

    Article  Google Scholar 

  • Burdick MD, Murray LA, Keane MP et al (2005) CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 171:261–268

    Article  PubMed  Google Scholar 

  • Capper ER, Maskill JK, Gordon C et al (2004) Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology? Clin Exp Immunol 138:348–356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • D’Cruz D, Khamashta MA, Hughes G (2007) Pulmonary manifestations of systemic lupus erythematosus. In: Wallace DJ, Hahn BH (eds) Dubois’ lupus erythematosus, 7th edn. Lippincott Williams & Wilkins, Philadelphia, pp 678–699

    Google Scholar 

  • Elia G (2015) Interferon-γ-inducible chemokines in systemic lupus erythematosus. Clin Ter 166:e41–e46

    CAS  PubMed  Google Scholar 

  • Eriksson C, Eneslätt K, Ivanoff J et al (2003) Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus. Lupus 12:766–774

    Article  CAS  PubMed  Google Scholar 

  • Galligan CL, Matsuyama W, Matsukawa A, Mizuta H et al (2004) Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum 50:1806–1814

    Article  CAS  PubMed  Google Scholar 

  • Groen H, Aslander M, Bootsma H et al (1993) Bronchoalveolar lavage cell analysis and lung function impairment in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 94:127–133

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    Article  CAS  PubMed  Google Scholar 

  • Jiang D, Liang J, Hodge J et al (2004) Regulation of pulmonary fibrosis by chemokine receptor CXCR3. J Clin Invest 114:291–299

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kao AH, Sabatine JM, Manzi S (2004) Lung disease in lupus. In: Wells AU, Denton ChP (eds) Pulmonary involvement in systemic autoimmune diseases. Elsevier, Boston, pp 125–246

    Google Scholar 

  • Keane MP, Arenberg DA, Lynch JP III et al (1997) The CXC chemokines, IL-8 and CXCL10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 159:1437–1443

    CAS  PubMed  Google Scholar 

  • Keane MP, Belperio JA, Arenberg DA et al (1999) IFNγ-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol 163:5686–5692

    CAS  PubMed  Google Scholar 

  • Keane MP, Belperio JA, Burdick MD et al (2001) ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 164:2239–2242

    Article  CAS  PubMed  Google Scholar 

  • Knall C, Young S, Nick JA et al (1996) Interleukin-8 regulation of the Ras/Raf/mitogenactivated protein kinase pathway in human neutrophils. J Biol Chem 271:2832–2838

    Article  CAS  PubMed  Google Scholar 

  • Kong KO, Tan AW, Thong BY et al (2009) Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus. Clin Exp Immunol 156:134–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • La Cava AL (2009) Lupus and T cells. Lupus 18:196–201

    Article  PubMed  Google Scholar 

  • Lee EY, Lee ZH, Song YW (2009) CXCL10 and autoimmune diseases. Autoimmun Rev 8:379–383

    Article  CAS  PubMed  Google Scholar 

  • Lit LC, Wong CK, Tam LS et al (2006) Raised plasma concentration and ex vivo production of inflammatory chemokines in patients with systemic lupus erythematosus. Ann Rheum Dis 65:209–215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lynch JP III, Standiford TJ, Rolfe MW et al (1992) Neutrophilic alveolitis in idiopathic pulmonary fibrosis: the role of interleukin-8. Am J Respir Crit Care Med 145:1433–1439

    Google Scholar 

  • Macintyre N, Crapo RO, Viegi G et al (2005) Standardization of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 26:720–735

    Article  CAS  PubMed  Google Scholar 

  • Miller MR, Hankinson J, Brusasco V et al (2005) Standardisation of spirometry. Eur Respir J 26:319–338

    Article  CAS  PubMed  Google Scholar 

  • Narumi S, Takeuchi T, Kobayashi Y et al (2000) Serum levels of IFN-inducible protein-10 relating to the activity of systemic lupus erythematosus. Cytokine 12:1561–1565

    Article  CAS  PubMed  Google Scholar 

  • Nielepkowicz-Goździńska A, Fendler W, Robak E et al (2014) Exhaled IL-8 in systemic lupus erythematosus with and without pulmonary fibrosis. Arch Immunol Ther Exp 62:231–238

    Article  Google Scholar 

  • Nor JE, Christensen J, Liu J et al (2001) Up-regulation of Bcl-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res 61:2183–2188

    CAS  PubMed  Google Scholar 

  • Okamoto H, Katsumata Y, Nishimura K et al (2004) Interferon-inducible protein 10/CXCL10 is increased in the cerebrospinal fluid of patients with central nervous system lupus. Arthritis Rheum 50:3731–3732

    Article  CAS  PubMed  Google Scholar 

  • Pan J, Burdick MD, Belperio JA et al (2006) CXCR3/CXCR3 ligand biological axis impairs RENCA tumor growth by a mechanism of immunoangiostasis. J Immunol 176:1456–1464

    Article  CAS  PubMed  Google Scholar 

  • Pantelidis P, Southcott AM, Black CM et al (1997) Up-regulation of IL-8 secretion by alveolar macrophages from patients with fibrosis alveolitis: a subpopulation analysis. Clin Exp Immunol 108:95–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Renzoni EA, Walsh DA, Salmon M et al (2003) Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 167:438–443

    Article  PubMed  Google Scholar 

  • Shah D, Wanchu A, Bhatnagar A (2011) Interplay of cytokines and chemokines in the pathogenesis of systemic lupus erythematosus. Am J Immunol 7:29–38

    Article  CAS  Google Scholar 

  • Strieter RM, Belperio JA, Keane MP (2002) CXC chemokines in angiogenesis related to pulmonary fibrosis. Chest 122(6 suppl):298S–301S

    Article  CAS  PubMed  Google Scholar 

  • Strieter RM, Gomperts BN, Keane MP (2007) The role of CXC chemokines in pulmonary fibrosis. J Clin Invest 117:549–556

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Szekanecz Z, Szücs G, Szántó S, Koch AE (2006) Chemokines in rheumatic diseases. Curr Drug Targets 7:91–102

    Article  CAS  PubMed  Google Scholar 

  • Tager AM, Kradin RL, LaCamera P et al (2004) Inhibition of pulmonary fibrosis by the chemokine CXCL10/CXCL10. Am J Respir Cell Mol Biol 31:395–404

    Article  CAS  PubMed  Google Scholar 

  • Tensen CP, Flier J, Van Der Raaij-Helmer EM et al (1999) Human IP-9: a keratinocyte-derived high affinity CXC-chemokine ligand for the CXCL10/CXCL9 receptor (CXCR3). J Invest Dermatol 112:716–722

    Article  CAS  PubMed  Google Scholar 

  • Vielhauer V, Anders HJ, Schlondorff D (2007) Chemokines and chemokine receptors as therapeutic targets in lupus nephritis. Semin Nephrol 27:81–97

    Article  CAS  PubMed  Google Scholar 

  • Wallaert B, Dugas M, Dansin E et al (1990) Subclinical alveolitis in immunological systemic disorders. Transition between health and disease? Eur Respir J 3:1206–1216

    CAS  PubMed  Google Scholar 

  • Wanger J, Clausen JL, Coates A et al (2005) Standardisation of the measurement of lung volumes. Eur Respir J 26:511–522

    Article  CAS  PubMed  Google Scholar 

  • Witt C, Dörner T, Hiepe F et al (1996) Diagnosis of alveolitis in interstitial lung manifestation in connective tissue diseases: importance of late inspiratory crackles, 67 gallium scan and bronchoalveolar lavage. Lupus 5:606–612

    Article  CAS  PubMed  Google Scholar 

  • Ziegenhagen MW, Schrum S, Zissel G et al (1998) Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. J Investig Med 46:223–231

    CAS  PubMed  Google Scholar 

  • Ziegenhagen MW, Rothe ME, Schlaak M et al (2003) Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis. Eur Respir J 21:407–413

    Article  CAS  PubMed  Google Scholar 

  • Zlotnik A, Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12:121–127

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was funded from the Grant no. N N402 292336 of the Polish Ministry of Science and Higher Education.

Author information

Authors and Affiliations

  1. Department of General and Oncological Pneumology, Medical University of Lodz, Kopcińskiego 22, 90-153, Lodz, Poland

    Agnieszka Nielepkowicz-Goździńska & Adam Antczak

  2. Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland

    Wojciech Fendler

  3. Department of Dermatology and Venereology, Medical University of Lodz, Lodz, Poland

    Ewa Robak & Lilianna Kulczycka-Siennicka

  4. Department of Pneumonology and Allergy, Medical University of Lodz, Lodz, Poland

    Paweł Górski, Tadeusz Pietras & Małgorzata Pietrusińska

  5. Department of Molecular Bases of Medicine, Medical University of Lodz, Lodz, Poland

    Ewa Brzeziańska

Authors
  1. Agnieszka Nielepkowicz-Goździńska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wojciech Fendler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ewa Robak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lilianna Kulczycka-Siennicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paweł Górski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tadeusz Pietras
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ewa Brzeziańska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Małgorzata Pietrusińska
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adam Antczak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Agnieszka Nielepkowicz-Goździńska.

Ethics declarations

Conflict of interest

None declared.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nielepkowicz-Goździńska, A., Fendler, W., Robak, E. et al. The Role of CXC Chemokines in Pulmonary Fibrosis of Systemic Lupus Erythematosus Patients. Arch. Immunol. Ther. Exp. 63, 465–473 (2015). https://doi.org/10.1007/s00005-015-0356-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-015-0356-8

Keywords

Search

Navigation