The Role of the Pulmonary Microenvironment in Driving Transition From Systemic Sclerosis to Systemic Sclerosis–Associated Interstitial Lung Disease

REFERENCES

1. 1.↵
   1. Cottin V,
   2. Brown KK.

   Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir Res 2019;20:13.

   OpenUrlCrossRefPubMed
2. 2.↵
   1. Garrett SM,
   2. Baker Frost D,
   3. Feghali-Bostwick C.

   The mighty fibroblast and its utility in scleroderma research. J Scleroderma Relat Disord 2017;2:69-134.

   OpenUrlCrossRef
3. 3.↵
   1. Makol A,
   2. Nagaraja V,
   3. Amadi C,
   4. Pugashetti JV,
   5. Caoili E,
   6. Khanna D.

   Recent innovations in the screening and diagnosis of systemic sclerosis-associated interstitial lung disease. Expert Rev Clin Immunol 2023;19:613-26.

   OpenUrlPubMed
4. 4.↵
   1. Distler O,
   2. Assassi S,
   3. Cottin V, et al.

   Predictors of progression in systemic sclerosis patients with interstitial lung disease. Eur Respir J 2020;55:1902026.

   OpenUrlAbstract/FREE Full Text
5. 5.↵
   1. Khanna D,
   2. Lin CJF,
   3. Furst DE, et al.

   Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2020;8:963-74.

   OpenUrlPubMed
6. 6.↵
   1. Sato S,
   2. Shinohara S,
   3. Hayashi S, et al.

   Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity. Respir Res 2017;18:172.

   OpenUrlCrossRefPubMed
7. 7.↵
   1. Vonk MC,
   2. Smith V,
   3. Sfikakis PP,
   4. Cutolo M,
   5. Del Galdo F,
   6. Seibold JR.

   Pharmacological treatments for SSc-ILD: systematic review and critical appraisal of the evidence. Autoimmun Rev 2021;20:102978.

   OpenUrlPubMed
8. 8.↵
   1. Soare A,
   2. Ramming A,
   3. Avouac J,
   4. Distler JHW.

   Updates on animal models of systemic sclerosis. J Scleroderma Relat Disord 2016;1:266-76.

   OpenUrl
9. 9.↵
   1. Fields A,
   2. Potel KN,
   3. Cabuhal R,
   4. Aziri B,
   5. Stewart ID,
   6. Schock BC.

   Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses. Thorax 2022;78:799-807.

   OpenUrlPubMed
10. 10.↵
    1. Moher D,
    2. Liberati A,
    3. Tetzlaff J,
    4. Altman DG; PRISMA Group

    . Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement. Open Med 2009; 3:e123-30.

    OpenUrlCrossRefPubMed
11. 11.↵
    1. Borenstein M,
    2. Hedges LV,
    3. Higgins JPT,
    4. Rothstein HR.

    A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 2010;1:97-111.

    OpenUrlPubMed
12. 12.↵
    1. Borenstein M,
    2. Hedges LV,
    3. Higgins JPT,
    4. Rothstein HR

    , ed. Effect sizes based on means. In: Introduction to meta-analysis. Hoboken: John Wiley & Sons; 2009:21-32.
13. 13.↵
    1. Evangelou E,
    2. Ioannidis JPA.

    Meta-analysis methods for genome-wide association studies and beyond. Nat Rev Genet 2013;14:379-89.

    OpenUrlCrossRefPubMed
14. 14.↵
    1. Szklarczyk D,
    2. Kirsch R,
    3. Koutrouli M, et al.

    The STRING database in 2023: protein—protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 2023;51:D638-46.

    OpenUrlCrossRefPubMed
15. 15.↵
    1. Reichenberger F,
    2. Schauer J,
    3. Kellner K,
    4. Sack U,
    5. Stiehl P,
    6. Winkler J.

    Different expression of endothelin in the bronchoalveolar lavage in patients with pulmonary diseases. Lung 2001;179:163-74.

    OpenUrlCrossRefPubMed
16. 16.↵
    1. Meloni F,
    2. Caporali R,
    3. Marone Bianco A, et al

    . Cytokine profile of bronchoalveolar lavage in systemic sclerosis with interstitial lung disease: comparison with usual interstitial pneumonia. Ann Rheum Dis 2004;63:892-4.

    OpenUrlFREE Full Text
17. 17.↵
    1. Kowal-Bielecka O,
    2. Kowal K,
    3. Lewszuk A,
    4. Bodzenta-Lukaszyk A,
    5. Walecki J,
    6. Sierakowski S.

    Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis. Ann Rheum Dis 2005;64:484-6.

    OpenUrlAbstract/FREE Full Text
18. 18.↵
    1. Fietta AM,
    2. Bardoni AM,
    3. Salvini R, et al.

    Analysis of bronchoalveolar lavage fluid proteome from systemic sclerosis patients with or without functional, clinical and radiological signs of lung fibrosis. Arthritis Res Ther 2006;8:R160.

    OpenUrlCrossRefPubMed
19. 19.↵
    1. Andersen GN,
    2. Nilsson K,
    3. Pourazar J, et al.

    Bronchoalveolar matrix metalloproteinase 9 relates to restrictive lung function impairment in systemic sclerosis. Respir Med 2007;101:2199-206.

    OpenUrlCrossRefPubMed
20. 20.
    1. Prasse A,
    2. Pechkovsky DV,
    3. Toews GB, et al.

    CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum 2007;56:1685-93.

    OpenUrlCrossRefPubMed
21. 21.↵
    1. Schmidt K,
    2. Martinez-Gamboa L,
    3. Meier S, et al

    . Bronchoalveoloar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther 2009;11:R111.

    OpenUrlCrossRefPubMed
22. 22.↵
    1. Sfriso P,
    2. Cozzi F,
    3. Oliviero F, et al.

    CXCL11 in bronchoalveolar lavage fluid and pulmonary function decline in systemic sclerosis. Clin Exp Rheumatol 2012;30 Suppl 71:S71-5.

    OpenUrlPubMed
23. 23.↵
    1. De Santis M,
    2. Inzitari R,
    3. Bosello SL, et al

    . β-thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up. Respir Res 2011;12:22.

    OpenUrlCrossRefPubMed
24. 24.↵
    1. Hesselstrand R,
    2. Wildt M,
    3. Bozovic G, et al.

    Biomarkers from bronchoalveolar lavage fluid in systemic sclerosis patients with interstitial lung disease relate to severity of lung fibrosis. Respir Med 2013;107:1079-86.

    OpenUrlCrossRefPubMed
25. 25.↵
    1. Sakamoto N,
    2. Kakugawa T,
    3. Hara A, et al.

    Association of elevated α-defensin levels with interstitial pneumonia in patients with systemic sclerosis. Respir Res 2015;16:148.

    OpenUrlCrossRefPubMed
26. 26.↵
    1. Zhang M,
    2. Zhang L,
    3. Linning E, et al.

    Increased levels of HE4 (WFDC2) in systemic sclerosis: a novel biomarker reflecting interstitial lung disease severity? Ther Adv Chronic Dis 2020;11:2040622320956420.

    OpenUrlCrossRefPubMed
27. 27.↵
    1. Kowal-Bielecka O,
    2. Kowal K,
    3. Highland KB,
    4. Silver RM.

    Bronchoalveolar lavage fluid in scleroderma interstitial lung disease: technical aspects and clinical correlations: review of the literature. Semin Arthritis Rheum 2010;40:73-88.

    OpenUrlCrossRefPubMed
28. 28.↵
    1. Kim W-U,
    2. Min S-Y,
    3. Cho M-L, et al

    . Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res Ther 2004;7:R71-9.

    OpenUrlPubMed
29. 29.↵
    1. Espindola MS,
    2. Habiel DM,
    3. Coelho AL, et al.

    Differential responses to targeting matrix metalloproteinase 9 in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2021;203:458-70.

    OpenUrlCrossRefPubMed
30. 30.↵
    1. Raeeszadeh-Sarmazdeh M,
    2. Coban M,
    3. Mahajan S, et al

    . Engineering of tissue inhibitor of metalloproteinases TIMP-1 for fine discrimination between closely related stromelysins MMP-3 and MMP-10. J Biol Chem 2022;298:101654.

    OpenUrlPubMed
31. 31.↵
    1. Ciechomska M,
    2. Huigens CA,
    3. Hügle T, et al

    . Toll-like receptor-mediated, enhanced production of profibrotic TIMP-1 in monocytes from patients with systemic sclerosis: role of serum factors. Ann Rheum Dis 2013;72:1382-9.

    OpenUrlAbstract/FREE Full Text
32. 32.↵
    1. Bingle L,
    2. Cross SS,
    3. High AS, et al.

    WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir Res 2006;7:61.

    OpenUrlCrossRefPubMed
33. 33.↵
    1. LeBleu VS,
    2. Teng Y,
    3. O’Connell JT, et al

    . Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat Med 2013;19:227-31.

    OpenUrlCrossRefPubMed
34. 34.↵
    1. Huang X,
    2. Guo X,
    3. Yan G, et al.

    Dapagliflozin attenuates contrast-induced acute kidney injury by regulating the HIF-1α/HE4/NF-κB pathway. J Cardiovasc Pharmacol 2022;79:904-13.

    OpenUrlPubMed
35. 35.↵
    1. Chrysanthopoulou A,
    2. Mitroulis I,
    3. Apostolidou E, et al.

    Neutrophil extracellular traps promote differentiation and function of fibroblasts. J Pathol 2014;233:294-307.

    OpenUrlCrossRefPubMed
36. 36.↵
    1. Ichimura Y,
    2. Kawaguchi Y,
    3. Takagi K,
    4. Tochimoto A,
    5. Higuchi T,
    6. Yamanaka H.

    FRI0473 Mpo-anca positivity is related to interstitial lung disease in systemic sclerosis. Ann Rheum Dis 2018;77:764-5.

    OpenUrl
37. 37.↵
    1. Yamakawa H,
    2. Toyoda Y,
    3. Baba T, et al.

    Anti-inflammatory and/or anti-fibrotic treatment of MPO-ANCA-positive interstitial lung disease: a short review. J Clin Med 2022;11:3835.

    OpenUrlPubMed
38. 38.↵
    1. Zagai U,
    2. Lundahl J,
    3. Klominek J,
    4. Venge P,
    5. Sköld CM.

    Eosinophil cationic protein stimulates migration of human lung fibroblasts in vitro. Scand J Immunol 2009;69:381-6.

    OpenUrlCrossRefPubMed
39. 39.↵
    1. Ando K,
    2. Nakashita T,
    3. Kaneko N,
    4. Takahashi K,
    5. Motojima S.

    Associations between peripheral blood eosinophil counts in patients with systemic sclerosis and disease severity. Springerplus 2016;5:1401.

    OpenUrlPubMed
40. 40.↵
    1. Pellicano C,
    2. Vantaggio L,
    3. Colalillo A, et al.

    Type 2 cytokines and scleroderma interstitial lung disease. Clin Exp Med 2023; 23:3517-25.

    OpenUrlPubMed
41. 41.↵
    1. Bouros D,
    2. Wells AU,
    3. Nicholson AG, et al.

    Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165:1581-6.

    OpenUrlCrossRefPubMed
42. 42.↵
    1. Kita H,
    2. Horie S,
    3. Gleich GJ.

    Extracellular matrix proteins attenuate activation and degranulation of stimulated eosinophils. J Immunol 1996;156:1174-81.

    OpenUrlAbstract
43. 43.↵
    1. Vega-Rioja A,
    2. Chacón P,
    3. Fernández-Delgado L, et al

    . Regulation and directed inhibition of ECP production by human neutrophils. Front Immunol 2022;13:1015529.

    OpenUrlPubMed
44. 44.↵
    1. Thorey IS,
    2. Roth J,
    3. Regenbogen J, et al.

    The Ca2+-binding proteins S100A8 and S100A9 are encoded by novel injury-regulated genes. J Biol Chem 2001;276:35818-25.

    OpenUrlAbstract/FREE Full Text
45. 45.↵
    1. Xu X,
    2. Chen H,
    3. Zhu X, et al.

    S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-κB-dependent pathways. Clin Exp Immunol 2013;173:523-35.

    OpenUrlCrossRefPubMed
46. 46.↵
    1. Hara A,
    2. Sakamoto N,
    3. Ishimatsu Y, et al.

    S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis. In: Respir Med 2012;106:571-80.

    OpenUrlCrossRefPubMed
47. 47.↵
    1. Miura S,
    2. Iwamoto H,
    3. Namba M, et al.

    High S100A9 level predicts poor survival, and the S100A9 inhibitor paquinimod is a candidate for treating idiopathic pulmonary fibrosis. BMJ Open Respir Res 2024;11:e001803.

    OpenUrlAbstract/FREE Full Text
48. 48.↵
    1. Luo Z,
    2. Lei H,
    3. Sun Y,
    4. Liu X,
    5. Su D-F.

    Orosomucoid, an acute response protein with multiple modulating activities. J Physiol Biochem 2015;71:329-40.

    OpenUrlCrossRefPubMed
49. 49.↵
    1. Wang PY,
    2. Feng JY,
    3. Zhang Z, et al.

    The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway. Acta Pharmacol Sin 2022;43:367-75.

    OpenUrlPubMed
50. 50.↵
    1. Smeets MB,
    2. Fontijn J,
    3. Kavelaars A,
    4. Pasterkamp G,
    5. De Kleijn DPV.

    The acute phase protein haptoglobin is locally expressed in arthritic and oncological tissues. Int J Exp Pathol 2003;84:69-74.

    OpenUrlCrossRefPubMed
51. 51.↵
    1. Lee PL,
    2. Lee KY,
    3. Cheng TM, et al.

    Relationships of haptoglobin phenotypes with systemic inflammation and the severity of chronic obstructive pulmonary disease. Sci Rep 2019;9:189.

    OpenUrlPubMed
52. 52.↵
    1. Quaye IK.

    Haptoglobin, inflammation and disease. Trans R Soc Trop Med Hyg 2008;102:735-42.

    OpenUrlCrossRefPubMed
53. 53.↵
    1. Berkova N,
    2. Gilbert C,
    3. Goupil S,
    4. Yan J,
    5. Korobko V,
    6. Naccache PH.

    TNF-induced haptoglobin release from human neutrophils: pivotal role of the TNF p55 Receptor1. J Immunol 1999;162:6226-32.

    OpenUrlAbstract/FREE Full Text
54. 54.↵
    1. Wang Y,
    2. Kinzie E,
    3. Berger FG,
    4. Lim SK,
    5. Baumann H.

    Haptoglobin, an inflammation-inducible plasma protein. Redox Rep 2001; 6:379-85.

    OpenUrlCrossRefPubMed
55. 55.↵
    1. Saraswat M,
    2. Joenväärä S,
    3. Tohmola T, et al

    . Label. Label-free plasma proteomics identifies haptoglobin-related protein as candidate marker of idiopathic pulmonary fibrosis and dysregulation of complement and oxidative pathways. Sci Rep 2020;10:7787.

    OpenUrlCrossRefPubMed
56. 56.↵
    1. Khanna D,
    2. Tashkin DP,
    3. Denton CP,
    4. Renzoni EA,
    5. Desai SR,
    6. Varga J.

    Etiology, risk factors, and biomarkers in systemic sclerosis with interstitial lung disease. Am J Respir Crit Care Med 2020; 201:650-60.

    OpenUrlPubMed
57. 57.↵
    1. Gould JM,
    2. Weiser JN.

    Expression of C-reactive protein in the human respiratory tract. Infect Immun 2001;69:1747-54.

    OpenUrlAbstract/FREE Full Text
58. 58.↵
    1. Yan B,
    2. Ren Y,
    3. Liu C,
    4. Shu L,
    5. Wang C,
    6. Zhang L.

    Cystatin SN in type 2 inflammatory airway diseases. J Allergy Clin Immunol 2023;151:1191-1203.e3.

    OpenUrl
59. 59.↵
    1. O’Reilly S.

    Senescence in diffuse systemic sclerosis is elevated and may play a role in fibrosis. Clin Exp Immunol 2025;219:uxad077.

    OpenUrlPubMed
60. 60.↵
    1. Ramirez GA,
    2. Franchini S,
    3. Rovere-Querini P,
    4. Sabbadini MG,
    5. Manfredi AA,
    6. Maugeri N.

    The role of platelets in the pathogenesis of systemic sclerosis. Front Immunol 2012;3:160.

    OpenUrlPubMed
61. 61.↵
    1. Senior RM,
    2. Griffin GL,
    3. Huang JS,
    4. Walz DA,
    5. Deuel TF.

    Chemotactic activity of platelet alpha granule proteins for fibroblasts. J Cell Biol 1983;96:382-5.

    OpenUrlAbstract/FREE Full Text
62. 62.↵
    1. Affandi AJ,
    2. Carvalheiro T,
    3. Ottria A, et al.

    CXCL4 drives fibrosis by promoting several key cellular and molecular processes. Cell Rep 2022;38:110189.

    OpenUrlCrossRefPubMed
63. 63.↵
    1. van Bon L,
    2. Affandi AJ,
    3. Broen J, et al

    . Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 2014;370:433-43.

    OpenUrlCrossRefPubMed
64. 64.↵
    1. Hinchcliff M,
    2. Khanna D,
    3. De Lorenzis E, et al

    . Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: a retrospective cohort study. Lancet Rheumatol 2025;7:e403-14.

    OpenUrlPubMed
65. 65.↵
    1. Antinozzi C,
    2. Corinaldesi C,
    3. Riccieri V, et al.

    OP0091 Cxcl10/cxcl11 serum measurement as potential predictor of systemic sclerosis. Ann Rheum Dis 2018;77:96.

    OpenUrl
66. 66.↵
    1. Assassi S,
    2. Li N,
    3. Volkmann ER, et al.

    Predictive significance of serum interferon-inducible protein score for response to treatment in systemic sclerosis-related interstitial lung disease. Arthritis Rheumatol 2021;73:1005-13.

    OpenUrlPubMed
67. 67.↵
    1. Burdick MD,
    2. Murray LA,
    3. Keane MP, et al.

    CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005;171:261-8.

    OpenUrlCrossRefPubMed
68. 68.↵
    1. He C,
    2. Ryan AJ,
    3. Murthy S,
    4. Carter AB.

    Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages. J Biol Chem 2013;288:20745-57.

    OpenUrlAbstract/FREE Full Text
69. 69.↵
    1. Gao F,
    2. Kinnula VL,
    3. Myllärniemi M,
    4. Oury TD.

    Extracellular superoxide dismutase in pulmonary fibrosis. Antioxid Redox Signal 2008;10:343-54.

    OpenUrlCrossRefPubMed
70. 70.↵
    1. Lei X,
    2. Du L,
    3. Yu W,
    4. Wang Y,
    5. Ma N,
    6. Qu B.

    GSTP1 as a novel target in radiation induced lung injury. J Transl Med 2021;19:297.

    OpenUrlPubMed
71. 71.↵
    1. Cui J,
    2. Li G,
    3. Yin J, et al.

    GSTP1 and cancer: expression, methylation, polymorphisms and signaling (review). Int J Oncol 2020;56:867-78.

    OpenUrlCrossRefPubMed
72. 72.↵
    1. Pan T,
    2. Sun J,
    3. Zhou J, et al.

    Function and mode of action of cytohesins in the epidermal growth factor pathway in colorectal cancer cells. Oncol Lett 2013;5:521-6.

    OpenUrlPubMed
73. 73.↵
    1. Wang Y,
    2. Çil Ç,
    3. Harnett MM,
    4. Pineda MA.

    Cytohesin-2/ARNO: A novel bridge between cell migration and immunoregulation in synovial fibroblasts. Front Immunol 2021;12:809896.

    OpenUrlPubMed
74. 74.↵
    1. Balanescu P,
    2. Balanescu E,
    3. Baicus C,
    4. Balanescu A.

    S100A6, calumenin and cytohesin 2 as biomarkers for cutaneous involvement in systemic sclerosis patients: a case control study. J Pers Med 2021;11:368.

    OpenUrlPubMed
75. 75.↵
    1. Bill A,
    2. Schmitz A,
    3. König K,
    4. Heukamp LC,
    5. Hannam JS,
    6. Famulok M.

    Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells. PLoS One 2012;7:e41179.

    OpenUrlCrossRefPubMed
76. 76.↵
    1. Bhattacharjee S,
    2. Das BB.

    Mitochondrial topoisomerases, nucleoid architecture and mtDNA repair in human disease. J Cell Sci 2025;138:jcs263638.

    OpenUrlPubMed
77. 77.↵
    1. Sobek S,
    2. Boege F.

    DNA topoisomerases in mtDNA maintenance and ageing. Exp Gerontol 2014;56:135-41.

    OpenUrlCrossRefPubMed
78. 78.↵
    1. Boonstra M,
    2. Bakker JA,
    3. Grummels A, et al.

    Association of anti-topoisomerase I antibodies of the IgM isotype with disease progression in anti-topoisomerase I-positive systemic sclerosis. Arthritis Rheumatol 2020;72:1897-904.

    OpenUrlPubMed
79. 79.↵
    1. Khanna D,
    2. Distler O,
    3. Cottin V, et al.

    Diagnosis and monitoring of systemic sclerosis-associated interstitial lung disease using high-resolution computed tomography. J Scleroderma Relat Disord 2022;7:168-78.

    OpenUrlPubMed