Blocking Focal adhesion kinase (FAK) protects against damage in a novel model of lymphocyte dominant lung injury

Abstract

Murine models help us understand human lung injuries by modeling the evolution of inflammation. Models of interstitial lung disease and hypersensitivity pneumonitis (HP) can identify targets to prevent fibrosis and preserve lung function.

We present a novel mouse model of lymphocyte dominant lung injury as well as a therapeutic target for attenuating inflammation: focal adhesion kinase (FAK). Six-week, adjuvant-free intranasal ovalbumin (ova) sensitization and challenge increased leukocytes in bronchoalvolar lavage (BAL) fluid. Previous studies demonstrated Th2 responses to ova dominated by eosinophils, while our new model provoked a lymphocyte predominant response, similar to HP. Lung intravital microscopy showed severe vascular leakage with increased leukocyte trafficking. Histology and immunofluorescence showed airway thickening, increased mucus production and extensive B220+cell infiltration consistent with a sustained inflammatory response.

FAK regulates leukocyte recruitment and affects lung fibrosis. A FAK inhibitor, PF-573228, was administered at the same time as ova during both the sensitization and challenge phases. We found that inhibiting FAK prevented leukocyte infiltration into the BAL and decreased production of pro-inflammatory cytokines. In summary, inhibition of FAK preserved lung architecture, prevented vascular leakage and limited leukocyte recruitment.

Our data suggest that a chronic adjuvant-free ovalbumin model is useful for examining chronic lung inflammation in mice and that FAK plays a previously unrecognized role in regulating inflammation.