LAUSR

Chronic lung allograft dysfunction (CLAD) is a major barrier limiting longterm survival after lung transplantation. Multiple pathophysiological mechanisms are involved, including inflammation, fibroblast proliferation, and extracellular matrix deposition. Dysregulated epithelial repair and airway remodeling are key features in the pathogenesis of bronchiolitis obliterans syndrome (BOS).1 Multiple growth factors, secreted by epithelial cells, fibroblasts, and inflammatory cells, are involved in this process, and transforming growth factor beta (TGFβ) plays a key role, by inducing fibroblast proliferation and differentiation into myofibroblasts.1 Epithelialtomesenchymal transition (EMT), the process by which the normal epithelium is replaced by fibroblastic scar tissue, is important in airway remodeling and is mainly believed to be driven by TGFβ1. During EMT, epithelial cells lose their epithelial properties and acquire a mesenchymal cell phenotype, including the deposition of extracellular matrix and production of matrix metalloproteinases.1 In this issue, Rahman and colleagues highlight the possible role of serine– threonine kinase 11, also known as liver kinase B1 (LKB1), in the process of EMT in CLAD after lung transplantation.2 LKB1 is a protein kinase that activates several downstream kinases by phosphorylating adenosine monophosphateactivated protein kinase (AMPK), and hereby regulates cell growth, cell polarity, cell metabolism, and autophagy.2 LKB1 functions as a tumor suppressor gene and inhibits EMT, tissue fibrosis, and malignant transformation by activation of AMPK.2 A clear role has been established for the LKB1AMPK pathway in cancer, in which it suppresses EMT during tumor progression. However, its role in chronic respiratory diseases or the development of CLAD after lung transplantation is less clear. Rahman and colleagues demonstrate that LKB1 was significantly downregulated in patients with BOS.2 Further in vitro analyses of EMT in human bronchial epithelial cells showed dysregulated expression of mesenchymal markers in case of knockdown of LKB1. Similarly, after incubation of bronchial epithelial cells with exosomes isolated from BOS patients, LKB1 expression was inhibited and EMT markers were upregulated.2 In future research, it would be important to assess if these findings can be reproduced in primary human bronchial epithelial cells obtained from lung transplant recipients exposed to classical immunosuppressants. The effects of exosomes in CLAD development and progression have been investigated in recent studies.2 Exosomes are small vesicles that are induced after lung injury and can contain human leukocyte and lung selfantigens, major histocompatibility complex class II molecules, adhesion and costimulatory molecules, transcription factors, and 20Sproteasome.2 Rahman et al. demonstrate that exosomes released from transplanted lungs undergoing chronic rejection also contained inactivated LKB1, and this loss may subsequently stimulate EMT and contribute to the development and progression of CLAD.2 LKB1 expression was significantly lower in exosomes from BOS patients compared to stable lung transplant recipients, and exosomes from BOS patients induced EMT in human bronchial epithelial cells.2 Moreover, 6 months before the clinical diagnosis of BOS was made, LKB1 was already downregulated in exosomes, suggesting its role in the pathogenesis of CLAD.2 A similar mechanism to EMT might also occur in restrictive allograft syndrome, in which TGFβ1driven mesothelialtomesenchymal transition has been described in in vitro analyses by Sacreas et al.3 Unfortunately, there were no lung transplant recipients with restrictive allograft syndrome included in this study, and it would be interesting to investigate the role of LKB1 in this process, as is also mentioned by the authors. With respect to the pathways LKB1 is involved in, LKB1 acts a master upstream kinase, directly phosphorylating and activating AMPK and AMPKrelated kinases4 (Figure 1). LKB1 is also the upstream regulator of mammalian target of rapamycin (mTOR), and LKB1 and AMPK negatively regulate mTOR complex 1 through AMPK phosphorylation of raptor and tuberous sclerosis complex 2.4 mTOR complex 1 controls the translation of several cell growth regulators, such as cyclin D1, hypoxia inducible factor 1a and cMyc, which in turn promote cell cycle progression, cell growth, and angiogenesis.4 Thus, by downregulating LBK1, activation of mTOR may also promote dysregulation of autophagy, inflammation, cell growth and survival, and ultimately fibrosis. On the other hand, it is also possible that the effects of LKB1 are (partly) mediated via TGFβ, as expression of LKB1 affects TGFβinduced SMAD phosphorylation and signaling, and inhibition of LKB1 or AMPK enhanced the effects of TGFβ and EMT in cancer research. LKB1 may be required for TGFβmediated myofibroblast differentiation.5 More research into the complexity of these pathways and their wide range of effects is needed, as new targeted therapy (partially) blocking one or more pathways could be a possible treatment option for CLAD. However, many of these pathways have multiple roles, making it difficult to inhibit them completely. Interestingly, recent research has shown that metformin, an AMPK agonist, may be useful as