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Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model.

ABSTRACT: Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found recently in mouse models that transient activation of Hedgehog pathway following irradiation rescued salivary gland function by preserving salivary stem/progenitor cells, parasympathetic innervation and microvessels. Due to huge differences between salivary glands of rodents and humans, to examine the translational potential of this approach, we evaluated effects of Shh gene transfer in a miniature pig model of irradiation-induced hyposalivation. Methods: The right parotid of each pig was irradiated with a single dose of 20 Gray. Shh and control GFP genes were delivered into irradiated parotid glands by noninvasive retrograde ductal instillation of corresponding adenoviral vectors 4 or 16 weeks after irradiation. Parotid saliva was collected every two weeks. Parotid glands were collected 5 or 20 weeks after irradiation for histology, Western blot and qRT-PCR assays. Results: Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks, preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models, and also activated autophagy and inhibited fibrogenesis in irradiated glands. Conclusion: These data indicate the translational potential of transient activation of Hedgehog pathway to preserve salivary function following irradiation.

SUBMITTER: Hu L

PROVIDER: S-EPMC6134926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The mechanisms of diabetic renal injury remain unclear. Recent studies have shown that immunological and inflammatory elements play important roles in the initiation and development of diabetic nephropathy (DN). Toll-like receptors (TLRs) comprise a superfamily of innate immune system receptors. The roles and mechanisms of TLRs in the pathogenesis of diabetic renal lesions are mostly unknown. Compared with rodents, miniature pigs are more similar to humans with respect to metabolism, kidney structure, and immune system, and therefore represent an ideal large-animal model for DN mechanistic studies. A diabetes model was established by feeding miniature pigs with high-sugar and high-fat diets. Functional and pathological markers, expression and activation of endogenous TLR ligands [HSP70 (heat shock protein 70) and HMGB1], TLR1 to TLR11 and their downstream signaling pathway molecules (MyD88, IRAK-1, and IRF-3), nuclear factor ?B (NF-?B) signaling pathway molecules (IKK?, I?B?, and NF-?Bp65), inflammatory cytokines [IL-6 (interleukin-6), MIP-2, MCP-1, CCL5, and VCAM-1 (vascular cell adhesion molecule-1)], and infiltration of inflammatory cells were systematically evaluated. The expression of HSP70 was significantly increased in diabetic pig kidneys. The expression of MyD88-dependent TLR2, TLR4, TLR5, TLR7, TLR8, and TLR11 and their downstream signaling molecules MyD88 and phospho-IRAK-1 (activated IRAK-1), as well as that of MyD88-independent TLR3 and TLR4 and their downstream signaling molecule phospho-IRF-3 (activated IRF-3), was significantly up-regulated. The expression and activation of NF-?B pathway molecules phospho-IKK?, phospho-I?B?, NF-?Bp65, and phospho-NF-?Bp65 were significantly increased. Levels of IL-6, MIP-2, MCP-1, CCL5, VCAM-1, and macrophage marker CD68 were significantly increased in diabetic pig kidneys. These results suggested that the metabolic inflammation activated by TLRs might play an important role in diabetic renal injuries.

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Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model.

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