Chronic rhinosinusitis (CRS), one of the most prevalent chronic diseases in the USA. Its pathophysiology is not well understood, but proinflammatory mediators and immunoreactive products are thought to play a significant role in initiating and sustaining the inflammation and mucus hypersecretion observed clinically in the sinonasal mucosa of CRS patients. Expression array and bioinformatics analyses of sinus mucosa from children with CRS (n=6) and controls (n=6) showed that several inflammatory/immune response genes are markedly upregulated. Five of these genes, validated at the mRNA level in an independent set of tissues, will be further evaluated in this study: the chemokine ligands CXCL5 and CXCL13 (not previously associated with CRS), and serum amyloid A (SAA2), serpin B4 and defensin 21 (DEFB1), which are part of the innate immune system. Our microarray data also showed upregulation of glandular genes: desmoglein(DSG)3, keratin(KRT)14 and parathyroid-like hormone(PTHLH), as well as downregulation of two apoptosis gene, caspase(CASP)8 and CASP9 in CRS sinus mucosa. Upregulation of glandular genes is consistent with the submucosal gland hyperplasia manifested in the sinus tissues of CRS patients. The hypothesis to be tested is that inflammatory gene products expressed in the sinus mucosa of pediatric patients with CRS induce glandular hypertrophy/hyperplasia.
The first Aim will compare in vitro glandular acinar cell models following differentiation of primary epithelial cells from the lower and upper respiratory tracts, a system recently established in our laboratory. In subsequent Aims, the cellular localization and expression of the candidate proteins will be determined and quantified in control and CRS sinus mucosa tissues to assess their potential importance in CRS.
Aim 2 will also determine the expression and cellular localization of inflammatory/immune response genes products during differentiation of acinar cells, and will evaluate whether inflammatory (CXCL5, CXCL13) and innate immune mediators (SAA2, SERPINB4, and DEFB1) can induce glandular differentiation in vitro.
Aim 3 will determine the temporal expression of DSG3, KRT14, PTHLH, CASP8 and CASP9 proteins during glandular acinar formation in vitro and their response to inflammatory/immune mediator(s) during glandular differentiation. The significance of the study is that it will establish whether specific chemokines and innate defense molecules, which are upregulated in the sinus mucosa of CRS pediatric patients, initiate glandular differentiation and hyperplasia. It will provide information that will ultimately lead to an understanding of glandular differentiation and hyperplasia and ultimately to approaches for reversing these processes, thereby decreasing morbidity in CRS patients.
Chronic rhinosinusitis (CRS) is one of the most prevalent chronic diseases in the USA and affects both children and adults. All CRS patients have chronic inflammation of the sinus mucosa and mucus hypersecretion. The latter is due to an increased number of submucosal glands in the sinus mucosa, e.g. glandular hyperplasia. This project will evaluate the ability of specific inflammatory mediators, which are highly expressed in the sinus mucosa of CRS pediatric patients, to initiate glandular hyperplasia. The resultant information will contribute to our limited understanding of glandular differentiation in response to chronic stimuli in the sinus mucosa and ultimately will lead to new approaches for reversing glandular hyperplasia, thus decreasing mucin overproduction, and morbidity in CRS.
| Wu, Xiaofang; Mimms, Remy; Banigan, Maureen et al. (2015) Development of glandular models from human nasal progenitor cells. Am J Respir Cell Mol Biol 52:535-42 |
| Wu, Xiaofang; Mimms, Remy; Lima, Roberta et al. (2012) Localization of inflammatory mediators in pediatric sinus mucosa. Arch Otolaryngol Head Neck Surg 138:389-97 |
| Wu, Xiaofang; Peters-Hall, Jennifer R; Ghimbovschi, Svetlana et al. (2011) Glandular gene expression of sinus mucosa in chronic rhinosinusitis with and without cystic fibrosis. Am J Respir Cell Mol Biol 45:525-33 |
| Wu, Xiaofang; Amorn, Melissa M; Aujla, Pawandeep K et al. (2011) Histologic characteristics and mucin immunohistochemistry of cystic fibrosis sinus mucosa. Arch Otolaryngol Head Neck Surg 137:383-9 |
| Wu, Xiaofang; Peters-Hall, Jennifer R; Bose, Sumit et al. (2011) Human bronchial epithelial cells differentiate to 3D glandular acini on basement membrane matrix. Am J Respir Cell Mol Biol 44:914-21 |
