JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation

Area of Science:

• Immunology
• Pulmonology
• Rheumatology

Background:

• Rheumatoid arthritis (RA) commonly presents with pulmonary fibrosis, a condition whose treatment remains challenging.
• The efficacy of Janus kinase (JAK) inhibitors, established for RA, in treating associated pulmonary fibrosis is not well understood.

Purpose of the Study:

• To investigate the therapeutic potential of a JAK2 inhibitor, CEP33779 (CEP), in a rat model of RA-associated interstitial lung disease.
• To elucidate the molecular mechanisms underlying CEP's effects on joint swelling, pulmonary fibrosis, and associated inflammatory pathways.

Main Methods:

• Administration of CEP to a rat model of RA-associated interstitial lung disease.
• In vitro studies using HFL1 cells stimulated with TGF-β1 to assess p-JAK2 expression.
• Inhibition of JAK2, TGFβ-R1/2, and p-STAT3, or silencing of STAT3 and JAK2 in HFL1 cells to analyze protein expression and signaling pathways.

Main Results:

• CEP treatment significantly reduced joint swelling, inflammation, and pulmonary fibrosis in rats, including decreased IL-1β, IL-6, and collagen deposition.
• CEP administration lowered TGFβ-R2, p-SMAD, and p-STAT3 expression in rat lung tissues.
• Inhibition of JAK2 or STAT3 in HFL1 cells decreased p-STAT3, p-SMAD3, and ECM protein levels, suggesting a role for the JAK2/STAT pathway.

Conclusions:

• JAK2 inhibitors represent a potential novel immunotherapeutic strategy for managing RA and concurrently mitigating associated pulmonary fibrotic disease.
• The therapeutic mechanism likely involves the JAK2/STAT signaling pathway, leading to downregulation of p-STAT3 and subsequent effects on SMAD3 phosphorylation and extracellular matrix production.