Baricitinib Improves Pulmonary Fibrosis in Mice with Rheumatoid Arthritis-associated Interstitial Lung Disease by Inhibiting the Jak2/Stat3 Signaling Pathway

Overview

Journal Adv Rheumatol

Publisher Biomed Central

Specialty Rheumatology

Date 2023 Aug 28

PMID 37641106

Authors

Hongli Liu

Yan Yang

Jie Zhang

Xuelin Li

Affiliations

Soon will be listed here.

Abstract

Objective: The study explored improvements in pulmonary inflammation and fibrosis in a bovine type II collagen-induced rheumatoid arthritis-associated interstitial lung disease mouse model after treatment with baricitinib and the possible mechanism of action.

Methods: A rheumatoid arthritis-associated interstitial lung disease mouse model was established, siRNA Jak2 and lentiviral vectors were transfected with human embryonic lung fibroblast cells. And the levels of relevant proteins in mouse lung tissue and human embryonic lung fibroblasts were detected by Western blotting.

Results: The levels of JAK2, p-JAK2, p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were increased in the lung tissues of model mice (P < 0.5) and decreased after baricitinib intervention (P < 0.05). The expression levels of p-STAT3, p-SMAD3, SMA, TGFβR2, FN and COL4 were reduced after siRNA downregulation of the JAK2 gene (P < 0.01) and increased after lentiviral overexpression of the JAK2 gene (P < 0.01).

Conclusion: Baricitinib alleviated fibrosis in the lung tissue of rheumatoid arthritis-associated interstitial lung disease mice, and the mechanism of action may involve the downregulation of Smad3 expression via inhibition of the Jak2/Stat3 signaling pathway, with consequent inhibition of the profibrotic effect of transforming growth factor-β1.

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References

Finckh A, Gilbert B, Hodkinson B, Bae S, Thomas R, Deane K . Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022; 18(10):591-602. DOI: 10.1038/s41584-022-00827-y. View

Norton S, Koduri G, Nikiphorou E, Dixey J, Williams P, Young A . A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular manifestations in RA and their impact on outcome. Rheumatology (Oxford). 2012; 52(1):99-110. DOI: 10.1093/rheumatology/kes262. View

Wilsher M, Voight L, Milne D, Teh M, Good N, Kolbe J . Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med. 2012; 106(10):1441-6. DOI: 10.1016/j.rmed.2012.06.020. View

Singh N, Varghese J, England B, Solomon J, Michaud K, Mikuls T . Impact of the pattern of interstitial lung disease on mortality in rheumatoid arthritis: A systematic literature review and meta-analysis. Semin Arthritis Rheum. 2019; 49(3):358-365. DOI: 10.1016/j.semarthrit.2019.04.005. View

Hyldgaard C, Hilberg O, Pedersen A, Ulrichsen S, Lokke A, Bendstrup E . A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017; 76(10):1700-1706. DOI: 10.1136/annrheumdis-2017-211138. View

Bongartz T, Nannini C, Medina-Velasquez Y, Achenbach S, Crowson C, Ryu J . Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010; 62(6):1583-91. PMC: 4028137. DOI: 10.1002/art.27405. View

Huo R, Guo Q, Hu J, Li N, Gao R, Mi L . Therapeutic Potential of Janus Kinase Inhibitors for the Management of Interstitial Lung Disease. Drug Des Devel Ther. 2022; 16:991-998. PMC: 8985822. DOI: 10.2147/DDDT.S353494. View

Vicente-Rabaneda E, Atienza-Mateo B, Blanco R, Cavagna L, Ancochea J, Castaneda S . Efficacy and safety of abatacept in interstitial lung disease of rheumatoid arthritis: A systematic literature review. Autoimmun Rev. 2021; 20(6):102830. DOI: 10.1016/j.autrev.2021.102830. View

Wu E, Ambrosini R, Kottmann R, Ritchlin C, Schwarz E, Rahimi H . Reinterpreting Evidence of Rheumatoid Arthritis-Associated Interstitial Lung Disease to Understand Etiology. Curr Rheumatol Rev. 2019; 15(4):277-289. PMC: 6629516. DOI: 10.2174/1573397115666190116102451. View

10.

Ruan H, Luan J, Gao S, Li S, Jiang Q, Liu R . Fedratinib Attenuates Bleomycin-Induced Pulmonary Fibrosis via the JAK2/STAT3 and TGF-β1 Signaling Pathway. Molecules. 2021; 26(15). PMC: 8347567. DOI: 10.3390/molecules26154491. View

11.

Montero P, Milara J, Roger I, Cortijo J . Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms. Int J Mol Sci. 2021; 22(12). PMC: 8226626. DOI: 10.3390/ijms22126211. View

12.

Beyer C, Distler J . Tyrosine kinase signaling in fibrotic disorders: Translation of basic research to human disease. Biochim Biophys Acta. 2012; 1832(7):897-904. DOI: 10.1016/j.bbadis.2012.06.008. View

13.

Roskoski Jr R . Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2019; 144:19-50. DOI: 10.1016/j.phrs.2019.03.006. View

14.

DAlessandro M, Perillo F, Refini R, Bergantini L, Bellisai F, Selvi E . Efficacy of baricitinib in treating rheumatoid arthritis: Modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting. Int Immunopharmacol. 2020; 86:106748. DOI: 10.1016/j.intimp.2020.106748. View

15.

Feng G, Xue X, Gao M, Wang X, Shu Z, Mu N . Therapeutic effects of PADRE-BAFF autovaccine on rat adjuvant arthritis. Biomed Res Int. 2014; 2014:854954. PMC: 3984822. DOI: 10.1155/2014/854954. View

16.

Szapiel S, Elson N, Fulmer J, Hunninghake G, Crystal R . Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse. Am Rev Respir Dis. 1979; 120(4):893-9. DOI: 10.1164/arrd.1979.120.4.893. View

17.

Hubner R, Gitter W, Mokhtari N, Mathiak M, Both M, Bolte H . Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008; 44(4):507-11, 514-7. DOI: 10.2144/000112729. View

18.

Wang S, Liu M, Li X, Zhang J, Wang F, Zhang C . Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis. FASEB J. 2022; 36(6):e22336. DOI: 10.1096/fj.202101436R. View

19.

Xiong L, Xiong L, Ye H, Ma W . Animal models of rheumatoid arthritis-associated interstitial lung disease. Immun Inflamm Dis. 2020; 9(1):37-47. PMC: 7860593. DOI: 10.1002/iid3.377. View

20.

Sato T, Satooka H, Ichioka S, Maruo Y, Hirata T . Citrullinated fibrinogen is a target of auto-antibodies in interstitial lung disease in mice with collagen-induced arthritis. Int Immunol. 2020; 32(8):533-545. DOI: 10.1093/intimm/dxaa021. View