No effect of deleted in malignant brain tumors 1 deficiency on chemotherapy induced murine intestinal mucositis

Anders B Nexoe,Andreas A Pedersen,Steffen Husby,Uffe Holmskov,Sönke Detlefsen,Grith L Sorensen,Mathias Rathe,Sebastian Von Huth,Ping-Ping Jiang

doi:10.1038/s41598-021-94076-w

Abstract

Mucositis is a serious adverse effect of chemotherapeutic treatment. During intestinal mucositis, the mucosal barrier is compromised, increasing the risk of severe infections. Mucositis necessitates dose reduction or pauses in treatment, which affect the outcome of the treatment. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We have previously shown that jejunal DMBT1 expression is increased in piglets during chemotherapeutic treatment. We hypothesized that DMBT1 ameliorates doxorubicin-induced mucositis. Individually-caged Dmbt1+/+ (WT) and Dmbt1−/− (KO) female mouse littermates received intraperitoneal injections of either doxorubicin or saline. They were euthanized after three (D3) or seven days (D7). Weight loss was monitored every day, and serum citrulline levels were measured at termination. Intestinal tissue was analyzed for the expression of DMBT1 and proinflammatory cytokines (IL-1β, IL-6, and TNF). Specimens from the small intestines and colon were scored for inflammation and epithelial and mucosal architecture changes. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. We detected a significant increase in crypt depth in WT mice compared to that in KO mice on D3. In conclusion, DMBT1 does not affect doxorubicin-induced mucositis in mice.

Highlights

Mucositis is a serious adverse effect of chemotherapeutic treatment
Doxorubicin treatment induced a significant decrease in citrulline levels on D3 but not on D7 compared to saline injection
Since citrulline is a marker of functional enterocyte mass and absorption and gastrointestinal mucositis, these data indicate that the mice were still suffering from the effects of doxorubicin on D3 but were in the restitution phase on D727,28

Summary

Introduction

The mucosal barrier is compromised, increasing the risk of severe infections. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. Mucositis increases the risk of infections, and mucositis may lead to dose reduction or cessation of treatment, which can reduce s urvival[4,5,6]. We hypothesized that DMBT1 might confer protective effects during chemotherapy-induced mucositis. We tested this hypothesis in a murine model of doxorubicin-induced mucositis by comparing WT mice expressing DMBT1 (Dmbt1+/+) with DMBT1-deficient KO mice (Dmbt1−/−)

Methods

Results

Conclusion