Jeremiah A Alt1,2, Xuan Qin1, Abigail Pulsipher2, Quinn Orb1, Richard R Orlandi1, Jianxing Zhang2, Austin Schults3, Wanjian Jia3, Angela P Presson4, Glenn D Prestwich2, Siam Oottamasathien2,3. 1. Department of Surgery, Division of Head and Neck Surgery, Rhinology-Sinus and Skull Base Surgery Program, University of Utah School of Medicine, Salt Lake City, UT. 2. Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT. 3. Department of Surgery, Division of Pediatric Urology, University of Utah School of Medicine, Salt Lake City, UT. 4. Department of Internal Medicine, Division of Epidemiology, University of Utah, Salt Lake City, UT.
Abstract
BACKGROUND: Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that: (1) LL-37 topically delivered would elicit profound OE inflammation; and (2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells. METHODS: To test our hypothesis we challenged C57BL/6 mice intranasally with increasing concentrations of LL-37. At 24 hours tissues were examined histologically and scored for inflammatory cell infiltrate, edema, and secretory hyperplasia. In separate experiments, fluorescently conjugated LL-37 was instilled and tissues were examined at 0.5 and 24 hours. To test our last hypothesis, we performed tissue myeloperoxidase (MPO) assays for neutrophil activity and immunohistochemistry for tryptase to determine the mean number of mast cells per mm(2) . RESULTS: LL-37 caused increased inflammatory cell infiltrate, edema, and secretory cell hyperplasia of the sinonasal mucosa, with higher LL-37 concentrations yielding significantly more inflammatory changes (p < 0.01). Fluorescent LL-37 demonstrated global sinonasal epithelial binding and tissue distribution. Further, higher concentrations of LL-37 led to significantly greater MPO levels with dose-dependent increases in mast cell infiltration (p < 0.01). CONCLUSION: LL-37 has dramatic inflammatory effects in the OE mucosa that is dose-dependent. The observed inflammatory changes in the olfactory mucosa were associated with the infiltration of both neutrophils and mast cells. Our biologic model represents a new model to further investigate the role of LL-37 in OE inflammation.
BACKGROUND: Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that: (1) LL-37 topically delivered would elicit profound OE inflammation; and (2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells. METHODS: To test our hypothesis we challenged C57BL/6 mice intranasally with increasing concentrations of LL-37. At 24 hours tissues were examined histologically and scored for inflammatory cell infiltrate, edema, and secretory hyperplasia. In separate experiments, fluorescently conjugated LL-37 was instilled and tissues were examined at 0.5 and 24 hours. To test our last hypothesis, we performed tissue myeloperoxidase (MPO) assays for neutrophil activity and immunohistochemistry for tryptase to determine the mean number of mast cells per mm(2) . RESULTS:LL-37 caused increased inflammatory cell infiltrate, edema, and secretory cell hyperplasia of the sinonasal mucosa, with higher LL-37 concentrations yielding significantly more inflammatory changes (p < 0.01). Fluorescent LL-37 demonstrated global sinonasal epithelial binding and tissue distribution. Further, higher concentrations of LL-37 led to significantly greater MPO levels with dose-dependent increases in mast cell infiltration (p < 0.01). CONCLUSION:LL-37 has dramatic inflammatory effects in the OE mucosa that is dose-dependent. The observed inflammatory changes in the olfactory mucosa were associated with the infiltration of both neutrophils and mast cells. Our biologic model represents a new model to further investigate the role of LL-37 in OE inflammation.
Authors: Mark H Wenink; Kim C M Santegoets; John Butcher; Lenny van Bon; Femke G M Lamers-Karnebeek; Wim B van den Berg; Piet L C M van Riel; Iain B McInnes; Timothy R D J Radstake Journal: Arthritis Rheum Date: 2011-11
Authors: Robin Lindsay; Tiffani Slaughter; Joy Britton-Webb; Steven R Mog; Rich Conran; Monica Tadros; Natalie Earl; David Fox; John Roberts; William E Bolger Journal: Otolaryngol Head Neck Surg Date: 2006-05 Impact factor: 3.497
Authors: Min Wan; Anne M van der Does; Xiao Tang; Lennart Lindbom; Birgitta Agerberth; Jesper Z Haeggström Journal: J Leukoc Biol Date: 2014-02-18 Impact factor: 4.962
Authors: Jianxing Zhang; Xiaoyu Xu; Narayanam V Rao; Brian Argyle; Lindsi McCoard; William J Rusho; Thomas P Kennedy; Glenn D Prestwich; Gerald Krueger Journal: PLoS One Date: 2011-02-09 Impact factor: 3.240
Authors: Abigail Pulsipher; Xuan Qin; Andrew J Thomas; Glenn D Prestwich; Siam Oottamasathien; Jeremiah A Alt Journal: Int Forum Allergy Rhinol Date: 2016-11-11 Impact factor: 3.858
Authors: Ravi Holani; Anshu Babbar; Graham A D Blyth; Fernando Lopes; Humberto Jijon; Derek M McKay; Morley D Hollenberg; Eduardo R Cobo Journal: Gut Microbes Date: 2020-07-13