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. 2023:2:100016.
doi: 10.1016/j.jfscie.2022.100016. Epub 2022 Nov 17.

A combination treatment of low-dose dexamethasone and aspirin-triggered resolvin D1 reduces Sjögren syndrome-like features in a mouse model

Harim Tavares Dos Santos  1   2 , Frank Maslow  1   2 , Kihoon Nam  1   2 , Bryan Trump  3 , Gary A Weisman  2   4 , Olga J Baker  1   2   4
Affiliations

A combination treatment of low-dose dexamethasone and aspirin-triggered resolvin D1 reduces Sjögren syndrome-like features in a mouse model

Harim Tavares Dos Santos et al. JADA Found Sci. 2023.

Abstract

Background: Sjögren syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and diminished secretory function of the salivary glands. Dexamethasone (DEX) resolves dry mouth and lymphocytic infiltration; however, this treatment is difficult to maintain because of multiple adverse effects (eg, osteoporosis and skin thinning); likewise, aspirin-triggered resolvin D1 (AT-RvD1) increases saliva secretion but cannot eliminate lymphocytic infiltration. Previous studies showed that a combination of low-dose DEX with AT-RvD1 before disease onset prevents SS-like features in a mouse model; however, this is not clinically practical because there are no reliable indicators of SS before disease onset. Therefore, the authors applied the combined treatment at disease onset to show its efficacy and comparative lack of adverse effects, so that it may reasonably be maintained over a patient's lifetime.

Methods: NOD/ShiLtJ mice were treated with ethanol (vehicle control), high-dose DEX alone, AT-RvD1 alone, or a combination of low-dose DEX with AT-RvD1 at disease onset for 8 weeks. Then saliva flow rates were measured, and submandibular glands were harvested for histologic analyses.

Results: A combined treatment of low-dose DEX with AT-RvD1 significantly decreased mast cell degranulation and lymphocytic infiltration, increased saliva secretion, and restored apical aquaporin-5 expression in submandibular glands of NOD/ShiLtJ mice.

Conclusions: Low-dose DEX combined with AT-RvD1 reduces the severity of SS-like manifestation and prevents the development of advanced and potentially irreversible damage, all in a form that can reasonably be administered indefinitely without the need to cease treatment because of secondary effects.

Keywords: Salivary glands; inflammation; lipid mediators; resolvins; steroids.

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Figures

Figure 1
Figure 1
Diagram summarizing the treatments used in the study. Sjögren syndrome–like mice were randomly divided into 4 groups and treated twice a week for 8 weeks via tail vein injection: ethanol (vehicle control), high-dose dexamethasone (DEX), aspirin-triggered resolvin D1 (AT-RvD1), and low-dose DEX with AT-RvD1. After the indicated times, specimens were collected as described in the Methods section. The study was performed using protocols approved by the Institutional Animal Care and Use Committee and the Animal Research Reporting In Vivo Experiments guidelines, and figures were generated using biorender.com.
Figure 2
Figure 2
Combined treatment with low-dose dexamethasone (DEX) with aspirin-triggered resolvin D1 (AT-RvD1) reduces submandibular gland lymphocytic infiltration in submandibular glands of Sjögren syndrome–like mice. Mice were treated as described in the Methods section, and submandibular glands were harvested, sectioned, and stained with hematoxylin-eosin. A. Lymphocytic foci are shown within yellow dotted lines in which scale bars in low and high magnification images are 500 μm and 50 μm, respectively. B. Lymphocytic foci were quantified, and data were expressed as mean (SD), in which * indicates P = .001 and † indicates not significant.
Figure 3
Figure 3
Combined treatment with low-dose dexamethasone (DEX) with aspirin-triggered resolvin D1 (AT-RvD1) reduces mast cell degranulation in submandibular glands of Sjögren syndrome–like mice. Submandibular glands were harvested, formalin-fixed, paraffin-embedded, and sectioned. A. Mast cell degranulation in submandibular glands was observed using toluidine blue staining (red arrows), in which scale bars represent 50 μm. B. Chymase was detected with rabbit–anti-mouse chymase antibody (green; red arrows), and nuclei were stained for nucleic acids with 4′,6-diamidino-2-phenylindole (blue) with images analyzed using confocal microscopy. Representative fluorescence images are shown from 4 samples, in which scale bars represent 100 μm. C. Mast cell degranulation was quantified and expressed as mean (SD), in which * indicates P = .05.
Figure 4
Figure 4
Combined treatment with low-dose dexamethasone (DEX) with aspirin-triggered resolvin D1 (AT-RvD1) increases saliva secretion in Sjögren syndrome–like mice. Mice were treated as described in Methods. Then, saliva was collected after intraperitoneal injection with pilocarpine-hydrogen chloride (50 mg/kg) and isoproterenol (0.5 mg/kg). Results are representative of 5 mice per condition, and data are expressed as mean (SD) in which * indicates P = .01.
Figure 5
Figure 5
Combined treatment with low-dose dexamethasone (DEX) with aspirin-triggered resolvin D1 (AT-RvD1) enhances the expression and apical distribution of aquaporin-5 in submandibular glands of Sjögren syndrome–like mice. Submandibular glands were harvested, formalin-fixed, paraffin-embedded, and sectioned. Aquaporin-5 staining was detected with rabbit–anti-mouse aquaporin-5 (green), nuclei were stained with 4′,6-diamidino-2-phenylindole (blue), and images were analyzed using confocal microscopy. Representative fluorescence images from 4 samples, in which scale bars represent 25 μm. White arrows indicate basolateral staining, and red arrows indicate apical staining for aquaporin-5.
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