Pneumologie 2013; 67 - P06
DOI: 10.1055/s-0033-1345044

Role of JAK-STAT pathway in pulmonary fibrosis

J Eschenbrenner 1, 2, 3, W Janssen 1, 2, 3, B Kojonazarov 1, 2, 3, K Murmann 1, 2, 3, A Ghofrani 1, 2, 3, N Weissmann 1, 2, 3, F Grimminger 1, 2, 3, W Seeger 1, 2, 3, RT Schermuly 1, 2, 3
  • 1Universities of Gießen and Marburg Lung Centre (UGMLC)
  • 2Member of the German Lung Center, DZL
  • 3Excellence Cluster Cardio Pulmonary System (ECCPS)

Rationale: Prior studies suggested a constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) in pulmonary fibrosis. STAT3 is part of the Janus Kinase (JAK)-STAT pathway, which is important for developmental regulation, growth control, and hemostasis in multicellular organisms. Several mediators like Interleukin (IL)-4 and Il-13, and factors like Platelet Derived Growth Factor (PDGF), thrombin and angiotensin are involved in the pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). These mediators and factors are known to transduce their signal though the JAK-STAT pathway. Little is understood about the contribution of this pathway in the pathogenesis of pulmonary fibrosis. Therefore, we investigated the effects of AZD1480, an Adenosine-Triphosphate (ATP) competitive inhibitor of JAK1 and 2, in pulmonary fibrosis.

Methods: Pulmonary fibrosis was induced in mice by oropharyngeal instillation of 3,5 U/kg Bleomycin. 7 days after instillation, daily oral treatment with 50 mg/kg AZD1480, was started and continued for 14 days. Fluorescence Molecular Tomography combined with Computed Tomography (FMT-CT) and measurement of lung mechanics were performed on day 21. Fibrosis score was detected histologically.

Results: Instillation of Bleomycin in mice induced pulmonary fibrosis [increased fibrotic score, increased Respiratory system resistance (Rrs) and decreased Compliance (Crs)]. Treatment with AZD1480 led to a significant decrease in fibrotic score. FMT-CT showed a significant decrease of Matrix Metalloprotease (MMP)-signal in FMT-CT, both parameters reflect antifibrotic effects of JAK1 and 2. AZD1480 only had a slight effect on lung mechanic parameters like Crs, but displayed a decrease of Rrs compared to the placebo group.

Conclusions: Bleomycin causes significant pulmonary fibrosis. Treatment with AZD1480 induces a significant reduction of fibrotic tissue in the lung and a slight improvement of lung mechanic parameters. Thus, inhibition of the JAK-STAT pathway may offer a new therapeutic approach for IPF patients.