Chronic sinusitis is nearly universal in humans with cystic fibrosis (CF) and is accompanied by sinus hypoplasia (small sinuses). However, whether impaired sinus development is a primary feature of loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or a secondary consequence of chronic infection remains unknown. Our objective was to study the early pathogenesis of sinus disease in CF.
Connexins are the building blocks of gap junctions. In forming a gap junction, six connexins oligomerize to form a hexameric torus called a connexon. The number of gap junctions in a cell ranges from a few to over 105 and imparts to interconnected cells a uniform phenotype. The crucial role that gap junctions play in normal physiology is reflected by the diverse spectrum of human diseases in which allele variants of different gap junction genes are implicated. In particular, mutations in GJB2 are a major cause of autosomal recessive non-syndromic deafness. This discovery has impacted medical practice and makes it incumbent on clinicians to familiarize themselves with the genetic advances that are rapidly occurring in our field.
Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.
Cell tight junction proteins create a barrier between airway epithelial cells to limit paracellular transport from the apical to basolateral surface. This barrier can impede the entry of respiratory pathogens and toxins from the airway lumen into the systemic circulation. Mast cell-mediated inflammation in the human airway can cause a disruption of this barrier. Tryptase is one of the major mediators released by mast cells and has been studied extensively in diseases such as asthma, reflux, and sinusitis. We hypothesize that tryptase may play a role in airway paracellular permeability by disrupting the cell tight junction proteins.