*Purpose: Recently we demonstrated that tumor suppressor gene Liver Kinase B1 (LKB1) is down regulated in lung biopsies and in the circulating exosomes of lung transplant (LTx) recipients diagnosed with bronchiolitis obliterans syndrome. STRADα functions as a pseudokinase that consists of a STE20-like kinase domain which can bind to and regulate the subcellular localization and activity of LKB1. Therefore, we hypothesized that downregulation of LKB1 may be accompanied by down regulation of STRADα and both may serve as early biomarkers for LTx recipients at risk for developing chronic lung allograft dysfunction (CLAD).

*Methods: We employed a murine chronic lung allograft rejection model published by Mimura et al (Am J Pathol 2015;185:1564-1574) in which single LTx of B6D2F1 lungs into DBA/2J recipient develop CLAD (80%) by about 28 days following LTx. Control consisted of the recipient’s own lung. STRADα and LKB1 in circulating exosomes and transplanted lungs (days 14 and 34) were detected using western blot analysis (protein level) and by RT-PCR for messenger level. Lung antigens (K-alpha 1 tubulin and Collagen V) specific IFN-γ and TNF-α secreting cells in the spleen were enumerated using ELISpot.

*Results: Expression of STRADα (p=0.007) and LKB1 (p=0.002) in the transplanted lung was significantly lower on day 14 following LTx and remained down regulated until sacrifice on day 34 (p=0.001 and p=0.003 respectively). LKB1 protein levels were also downregulated in circulating exosomes after LTx (day 14, p=0.002 and day 34, p=0.0001). Immunohistology demonstrated increased fibrosis in LTx lungs compared to recipient lungs by day 34 (p=0.0007). ELISpot analysis demonstrated that splenocytes isolated from LTx mice had increased levels of lung self-antigen specific IFN-γ (Collagen V, 109±2.5; Kα1 Tubulin, 101±5.5) and TNF-α (Collagen V, 39±1.5; Kα1 Tubulin, 53±5.5).

*Conclusions: Downregulation of STRADα and LKB1 expression in the transplanted lung and circulating exosomes occur prior to development of chronic rejection following murine orthotopic LTx. We propose that STRADα may act as an up regulator of LKB1 and that downregulation of STRADα-LKB1 axis can induce immune responses to lung self-antigens and mediates epithelial to mesenchymal transition resulting in chronic rejection after LTx.

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