Post-Irradiated Human Submandibular Glands Display High Collagen Deposition, Disorganized Cell Junctions, and an Increased Number of Adipocytes

Nam, Ki Woong; Maruyama, Christina L.; Trump, Bryan; Buchmann, Luke; Hunt, Jason P.; Monroe, Marcus M.; Baker, Olga J.

doi:10.1369/0022155416646089

Cited by 22 publications

(14 citation statements)

References 37 publications

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“…Severe radiation injury to the salivary glands results in depletion of acinar cells, concomitant with ductal expansion, and an increase in fibrosis and inflammation (Cheng et al 2011; Nam et al 2016). Secretory cell loss appears to be a late effect, as SMG acinar cell depletion is not obvious at 2 or 6 wk following irradiation (Appendix Fig.…”

Section: Discussionmentioning

confidence: 99%

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

et al. 2018

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Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.

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Section: Discussionmentioning

confidence: 99%

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

et al. 2018

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“…In salivary glands of SS patients and NOD mice, the integrity of TJs is disrupted, including elevated Cldn1 and Cldn3 expression as well as reduced Cldn4, Ocln, and ZO‐1 expression (Zhang et al , 2016). ZO‐1 is also observed to be decreased in post‐irradiated human SMG (Nam et al , 2016). Moreover, the expression of ZO‐1, Cldn3, and Cldn11 are reduced in the hyposecretory SMG, whereas these TJ proteins levels are reversed with the restoration of SMG function (Cong et al , 2012; Yang et al , 2017).…”

Section: Discussionmentioning

confidence: 97%

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

et al. 2020

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Tight junction (TJ) plays an important role in regulating paracellular fluid transport in salivary glands; however, little is known about the involvement of TJs in diabetes salivary glands. This study aimed to investigate the alterations of TJs and their possible contribution in diabetes‐induced hyposalivation. Here, we observed that the morphologies of submandibular glands (SMGs) were impaired, characterized by enlarged acini accumulation with giant secretory granules, which were significantly reduced in atrophic ducts in SMGs of db/db mice, a spontaneous model of type‐2 diabetes. However, the secretory granules were increased and scattered in the acini of diabetes parotid glands (PGs). Other ultrastructural damages including swollen mitochondria, expansive endoplasmic reticulum, and autophagosomes were observed in the diabetes group. The levels of TJ proteins including claudin‐1 (Cldn1) and claudin‐3 (Cldn3) were increased, whereas those of claudin‐4 (Cldn4), occludin (Ocln), and zonula occludens‐1 (ZO‐1) were decreased in SMGs of db/db mice. Higher Cldn1 and Cldn3 and lower claudin‐10 (Cldn10) and Ocln levels were observed in PGs of diabetes mice. Taken together, the structures of SMGs and PGs were impaired in diabetes mice, and the disruption of TJ integrity in both SMGs and PGs may contribute to diabetes‐induced hyposalivation.

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“…In our study, the depletion of salivary ductal progenitors and acinar cells was observed 4 wk after IR and persisted 12 wk after IR. IR injury to the salivary glands depletes salivary gland progenitors and increases fibrosis and inflammation (Cheng et al 2011; Nam et al 2016). However, immunofluorescence analysis showed the preservation of KRT14 + basal ductal and MIST1 + acinar cells in SMGs subjected to retroductal EGF treatment before IR.…”

Section: Discussionmentioning

confidence: 99%

Retroductal Delivery of Epidermal Growth Factor Protects Salivary Progenitors after Irradiation

et al. 2021

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Salivary gland hypofunction after irradiation is associated with a deficit of epithelial stem/progenitors in salivary glands. Although epidermal growth factor (EGF) is known to stimulate the proliferation of epithelial cells, the therapeutic effect of EGF on salivary epithelial stem/progenitors remains undetermined. In this study, we administered EGF to submandibular glands (SMGs) via a retrograde route through the SMG excretory duct before fractionated irradiation and examined whether EGF could protect salivary epithelial progenitor cells from radiation and alleviate radiation-induced salivary hypofunction. EGF-treated mice exhibited greater body and gland weights at 12 wk after irradiation than untreated mice. The retroductal delivery of EGF improved salivary secretory function and increased salivary amylase activity in a dose-dependent manner. Histological examinations highlighted the amelioration of the loss of keratine-14+ (KRT14+) basal ductal and/or MIST1+ acinar cells, as well as induction of fibrosis, following irradiation in EGF-treated mice. An additional in vitro experiment using a salivary gland organoid irradiation model indicated that the radioprotective effects of EGF promoted the growth and inhibited the apoptotic cell death of salivary epithelial cells. Our results suggest that retroductal delivery of EGF may be a promising therapeutic option for preventing radiation-induced salivary gland hypofunction.

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Post-Irradiated Human Submandibular Glands Display High Collagen Deposition, Disorganized Cell Junctions, and an Increased Number of Adipocytes

Cited by 22 publications

References 37 publications

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection

Disruption of tight junctions contributes to hyposalivation of salivary glands in a mouse model of type 2 diabetes

Retroductal Delivery of Epidermal Growth Factor Protects Salivary Progenitors after Irradiation

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