Accumulating evidence suggests that gender impacts the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies suggests that sex hormones may contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.

Na ؉ ͞H ؉ exchanger regulatory factor (NHERF)-1 and NHERF-2, two structurally related protein adapters containing tandem PSD-95͞ Discs large͞ZO-1 (PDZ) domains, were identified as essential factors for protein kinase A-mediated inhibition of the sodium-hydrogen exchanger, NHE3. NHERF-1 and NHERF-2 also bound other cellular targets including the sodium-phosphate cotransporter type IIa encoded by the NPT2 gene. Targeted disruption of the mouse NHERF-1 gene eliminated NHERF-1 expression in kidney and other tissues of the mutant mice without altering NHERF-2 levels in these tissues. NHERF-1 (؉͞؊) and (؊͞؊) male mice maintained normal blood electrolytes but showed increased urinary excretion of phosphate when compared with wild-type (؉͞؉) animals. Although the overall levels of renal NHERF-1 targets, NHE3 and Npt2, were unchanged in the mutant mice, immunocytochemistry showed that the Npt2 protein was aberrantly localized at internal sites in the renal proximal tubule cells. The mislocalization of Npt2 paralleled a reduction in the transporter protein in renal brushborder membranes isolated from the mutant mice. In contrast, NHE3 was appropriately localized at the apical surface of proximal tubules in both wild-type and mutant mice. These data suggested that NHERF-1 played a unique role in the apical targeting and͞or trafficking of Npt2 in the mammalian kidney, a function not shared by NHERF-2 or other renal PDZ proteins. Phosphate wasting seen in the NHERF-1(؊͞؊) null mice provided a new experimental system for defining the role of PDZ adapters in the hormonal control of ion transport and renal disease.

NHERF (Na+/H+ exchanger regulatory factor or NHERF-1) and E3KARP (NHE3 kinase A regulatory protein or NHERF-2) are structurally related protein adapters that are highly expressed in epithelial tissues. NHERF proteins contain two tandem PDZ domains and a C-terminal sequence that binds several members of the ERM (ezrin-radixin-moesin) family of membrane-cytoskeletal adapters. Although identified as a regulator of NHE3, recent evidence points to a broadening role for NHERF in the function, localization and/or turnover of G-protein coupled receptors, platelet-derived growth factor receptor and ion transporters such as CFTR, Na/Pi cotransporter, Na/HCO3 cotransporter and Trp (calcium) channels. NHERF also recruits non-membrane proteins such as the c-Yes/YAP-65 complex, members of the phospholipase Cbeta family and the GRK6A protein kinase to apical surface of polarized epithelial cells where they regulate or respond to membrane signals. While two distinct models have been proposed for NHERF's role in signal transduction, the common theme is NHERF's ability to bring together membrane and non-membrane proteins to regulate cell metabolism and growth. NHERF overexpression in human breast cancers and mutations in NHERF targets, such as CFTR and merlin, the product of Neurofibromatosis NF2 tumor suppressor gene, that impair NHERF binding suggest that aberrant NHERF function contributes to human disease.