The majority of BHD patients develop pulmonary cysts and approximately 1 in 3 will suffer a pneumothorax. Although BHD pulmonary cysts have defining characteristics compared to other cystic lung diseases (as discussed in recent reviews), the underlying pathogenesis is not yet clearly understood. A recent review from Kennedy, Khabibullin & Henske (2016) summarises the current understanding of BHD pulmonary pathology relative to the stretch hypothesis for cyst formation.
The stretch hypothesis is based on reports of FLCN interacting with PKP4/p0071 to regulate cell-cell adhesion, with the loss of either protein increasing adhesive strength (Medvetz et al., 2012, Nahorski et al., 2012, Khabibullin et al., 2014). During respiration, due to less negative intrapleural pressure, the alveoli in the basal regions of the lungs undergo a greater change in volume than those in the apical regions. The stretch hypothesis suggests that defects in cell-cell adhesion in the areas of the lung repeatedly subjected to higher inspiration stretch-forces, including anchor points to the pleura, lead to failure of the septal wall and subsequent cyst formation. This is supported by the location of BHD pulmonary cysts, which are predominantly basilar and frequently abut pleura and blood vessels.
The loss of the FLCN-PKP4 complex could be impacting cell-cell adhesion in several ways. Abnormal expression and organisation of E-cadherin and Claudin-1, components of adherens and tight junctions respectively, were seen in mouse IMCD-3 renal epithelial cells after FLCN knockdown (Nahorski et al., 2012), and increased desmosome production was reported in FLCN-null human UOK-257 renal cells (Medvetz et al., 2012). This was associated with reduced transepithelial electrical resistance and disrupted cell polarity, resulting in additional cellular stress. E-cadherin expression was also reduced in primary mouse airway epithelial cells lacking Flcn (Goncharova et al, 2014) suggesting that the same disruptions could be contributing to pulmonary pathology.
It is still unclear whether pulmonary cystogenesis in BHD patients is due to haploinsufficiency or if a loss of the second FLCN allele is required, as with renal tumours. Furuya et al. (2012) reported expression of FLCN in BHD patient cysts, but a heterozygous Flcn+/- mouse model showed no airspaces enlargement at five months (Khabibullin et al. 2014). Interestingly alveolar enlargement was seen in mice where total Flcn loss was induced only in SP-C+ epithelial lung cells (Goncharova et al, 2014). This suggests a specific role for these cells in cyst formation, further supported by reports of SP-C+ epithelial cells lining BHD patient cysts (Furuya et al., 2012, Furuya & Nakatani, 2013) – however these cells still expressed some FLCN protein.
There are several other aspects of pulmonary pathogenesis in BHD patients that also require more research: when and how rapidly the cysts develop; why the risk of pneumothorax decreases with age; whether cystogenesis is due to inflammatory destruction, aberrant proliferation or both; and whether it is due to defects only in epithelial cells or if there is a role for mesenchyml cells. A clearer understanding of the complete pathogenic basis of cystogenesis in BHD patients could enable development of a treatment to reduce cyst formation thereby reducing the risk of pneumothorax.
- Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N, Moritani S, Mizuno H, Nagashima Y, Nagahama K, Hiroshima K, Yoshino I, Nomura F, Aoki I, Nakatani Y (2012). Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol. 36(4):589-600. PMID: 22441547.
- Furuya M, Nakatani Y (2013). Birt-Hogg-Dube syndrome: clinicopathological features of the lung. J Clin Pathol. 66(3):178-86. PMID: 23223565.
- Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, Li H, Gonzales L, Baba M, Linehan WM, Gow AJ, Margulies S, Guttentag S, Schmidt LS, Krymskaya VP (2014). Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell Rep. 7(2):412-23. PMID: 24726356.
- Kennedy JC, Khabibullin D, & Henske EP (2016). Mechanisms of Pulmonary Cyst Pathogenesis in Birt-Hogg-Dube Syndrome: The Stretch Hypothesis. Seminars in cell & developmental biology PMID: 26877139.
- Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, Laucho Contreras M, Zhang E, Parkhitko A, Yu JJ, Owen CA, Huang H, Baron RM, Henske EP (2014). Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiol Rep. 2(8). pii: e12107. PMID: 25121506.
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS One. 7(11):e47842. PMID: 23139756.
- Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet. 21(24):5268-79. PMID: 22965878.