Abstract
Introduction: Obliterative bronchiolitis (OB) occurs during chronic allograft rejection of lung transplantation. OB is characterized by airway epithelium degradation, and obstruction of the small airways with inflammatory infiltrate and fibrosis. MSK1 is a nuclear kinase that activates NFκB in inflammation. Our hypothesis proposes MSK1 as an actor in OB via NFκB-induced activation of pro-inflammatory genes like IL-6.
Methods: In the mouse model of heterotopic tracheal transplantation, tracheal MSK1 and IL-6 mRNA was quantified by qPCR. Mice were treated I.P. with compound H89, a MSK1 inhibitor (10mg/kg/day) vs solvent (DMSO 5%). Tracheal sections were stained with hematoxylin-eosin, and epithelium degradation measured. CD3+ cells (SP7 anti-CD3 mAb, Abcam) were counted and dendritic cells (DC, H2-I-A/I-E mAb, M5/114) labeled on fresh tracheas.
Results: MSK1 and IL-6 mRNA levels were increased in allografts by 68±8% and 88±2%, respectively, at D7 as compared to D0 and unmodified in isografts. Progressive epithelium degradation reached 77±4% of the total epithelium at D7 and was inhibited upon H89 treatment of 43±10% (p<0.05). In isografts, epithelium degradation also occurred (18±10%). CD3+ cell recruitment reached 208±82 cells/mm2 at D7 and was inhibited to 16±8 cells/mm2 (p<0.05), compared to isografts (17±9 cells/mm2, NS). DC recruitment also occurred in allografts (525±73 cells/mm2 at D3 and 1065±368 at D7) as compared to D0 (290±17). No effect of H89 was observed on DC recruitment at D3. Inflammatory luminal infiltrate was inhibited at D7 by 44±15%.
Conclusion: Inhibiting MSK1 is therefore a potential strategy to help combat obstruction after lung transplantation in this OB model.
- © 2011 ERS