Lung transplantation (LTx) is the only life-extending option for patients with end-stage lung diseases. Approximately half of LTx recipients (LTxRs) clinically diagnosed with chronic lung allograft dysfunction (CLAD) will experience chronic rejection within 5 years of transplant [1]. CLAD is defined as a substantial and persistent decline (≥20%) in measured forced expiratory volume in 1 second (FEV1) value from the reference (baseline) value. The baseline value is computed as the mean of the best 2 post-operative FEV1 measurements (taken >3 weeks apart) [2]. The prevalence of bronchiolitis obliterans syndrome (BOS), a condition in which the bronchioles become inflamed and fibrotic, a subtype of CLAD. The incidence ranges from 30-40% within 5 years, and BOS is the most significant cause of long-term graft failure and mortality after LTx [3]. CLAD results primarily from immunological insults to transplanted lungs. Significant correlations between BOS and post-transplant development of antibodies to mismatched donor human leukocyte antigens (HLAs), that is, donor-specific antibodies and antibodies to the lung self-antigens (SAgs), K-alpha 1 tubulin and Collagen V (Col-V), have been reported [4], [5].

Recent studies have shown that exosomes play an important role in gene expression [6], cellular signaling [7], epithelial mesenchymal transition [8], and disease progression [9]. Three types of extracellular vesicles have been classified according to their diameter: exosomes (30-200 nm), microvesicles (200-500 nm), and apoptotic bodies (500-1000 nm) [10]. Recently, our laboratory has demonstrated that exosomes isolated from BOS inhibit tumor suppressor gene liver kinase B1 (LKB1) expression and induce epithelial mesenchymal transition (EMT) in both HPBEC and BEAS-2B cells [11]. It has been shown that EMT plays an important role in airway remodeling [12] and Borthwick and colleagues [13] have demonstrated that EMT may underlie the dysfunctional airway repair processes that lead to obliterans bronchiolitis.

At present, the mechanism by which LKB1 affects BOS development is unknown, and therapeutic options to prevent or treat BOS are unavailable. It has also been reported that disruption of cellular polarity may induce fibrosis, a hallmark of CLAD [14], [15]. LKB1 is required to maintain cell polarity and control growth through protease-activated receptor-1 and AMP-activated protein kinase (AMPK), respectively [16], [17]. LKB1 plays a critical role in EMT [18], differentiation [19], migration [20], and mammalian target of rapamycin (mTOR) signaling [21]. EMT (or EMT-like processes) may affect the development of BOS after human LTx. Furthermore, increased phosphorylation of mTOR is closely associated with pulmonary fibrosis [22]. LKB1 signaling controls energy metabolism [23] and tissue homeostasis [24], and deletion of the LKB1 gene is embryonic-lethal [25]. Germline mutations in LKB1 are associated with a predisposition to Peutz-Jeghers syndrome [26], an inherited condition that increases cancer risk. Loss of LKB1 expression by either somatic mutations or promoter hypermethylation is frequently identified in several cancer types including lung cancer [27]. The role of LKB1 and its downstream regulators and the link to AMPK signals in the development of BOS after LTx have not been studied. STE20-related adaptor alpha (STRADα) functions as a pseudokinase that consists of an STE20-like kinase domain but lacks several residues required for intrinsic catalysis [28], [29]. STRADα is an essential co-factor for LKB1-mediated G1-phase cell cycle arrest [30], [31]. We examined the effect of STRADα on LKB1 expression.

In this study using a murine model of chronic lung allograft rejection (B6D2F1 to DBA/2J) [32], we demonstrated that the downregulation of the LKB1-STRADα axis modulated AMPK and mTOR phosphorylation which increase fibrosis of transplanted lung.