Mechanisms of pulmonary cyst pathogenesis in Birt-Hogg-Dube syndrome: The stretch hypothesis

Loss-of-function mutations in the folliculin gene (FLCN) on chromosome 17p cause Birt-Hogg-Dube syndrome (BHD), which is associated with cystic lung disease. The risk of lung collapse (pneumothorax) in BHD patients is 50-fold higher than in the general population. The cystic lung disease in BHD is distinctive because the cysts tend to be basilar, subpleural and lentiform, differentiating BHD from most other cystic lung diseases. Recently, major advances in elucidating the primary functions of the folliculin protein have been made, including roles in mTOR and AMPK signaling via the interaction of FLCN with FNIP1/2, and cell-cell adhesion via the physical interaction of FLCN with plakophilin 4 (PKP4), an armadillo-repeat containing protein that interacts with E-cadherin and is a component of the adherens junctions. In addition, in just the last three years, the pulmonary impact of FLCN deficiency has been examined for the first time. In mouse models, evidence has emerged that AMPK signaling and cell-cell adhesion are involved in alveolar enlargement. In addition, the pathologic features of human BHD cysts have been recently comprehensively characterized. The “stretch hypothesis” proposes that cysts in BHD arise because of fundamental defects in cell-cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in regions of the lung with larger changes in alveolar volume and at weaker “anchor points” to the pleura. This hypothesis ties together many of the new data from cellular and mouse models of BHD and from the human pathologic studies. Critical questions remain. These include whether the consequences of stretch-induced cyst formation arise through a destructive/inflammatory program or a proliferative program (or both), whether cyst initiation involves a “second hit” genetic event inactivating the remaining wild-type copy of FLCN (as is known to occur in BHD-associated renal cell carcinomas), and whether cyst initiation involves exclusively the epithelial compartment versus an interaction between the epithelium and mesenchyme. Ultimately, understanding the mechanisms of cystic lung disease in BHD may help to elucidate the pathogenesis of primary spontaneous pneumothorax, with more than 20,000 cases reported annually in the United States alone.