Chemotherapy-induced mucositis is associated with changes in proteolytic pathways.
Jonathan Leblond1, Florence Le Pessot, Aurélie Hubert-Buron
1Appareil Digestif Environnement Nutrition (EA3234), Institut Hospitalo-Universitaire de Recherche Biomédicale and Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP23), University of Rouen and Rouen University Hospital, France.
Experimental Biology and Medicine (Maywood, N.J.)
|January 29, 2008
Summary
Methotrexate chemotherapy causes mucositis by damaging the gut barrier and altering protein breakdown. Lysosomal enzyme activity, specifically cathepsin D, is linked to this gut damage and increased permeability.
Area of Science:
- Gastroenterology
- Oncology
- Cell Biology
Background:
- Mucositis is a severe chemotherapy side effect impacting gut integrity.
- Gut barrier function relies on protein synthesis and breakdown balance.
- Methotrexate (MTX) is a common chemotherapeutic agent known to cause toxicity.
Purpose of the Study:
- To investigate the effects of MTX on intestinal proteolysis and gut barrier function in rats.
- To identify the specific proteolytic pathways involved in MTX-induced mucositis.
Main Methods:
- Rats were administered MTX subcutaneously for 3 days.
- Intestinal permeability, mucosal damage, inflammatory markers (IL-1beta, IL-6), glutathione, and proteolytic enzyme activities (cathepsin D, proteasome, calpain) were assessed at Day 4 and Day 7.
- Villus height was measured.
Main Results:
- MTX induced significant mucosal damage, increased intestinal permeability (7-fold), and elevated IL-1beta and IL-6 levels at Day 4.
- Villus height and glutathione content decreased, while cathepsin D activity increased.
- Proteasome activity decreased, remaining reduced at Day 7, while cathepsin D normalized.
- Cathepsin D activity correlated with mucosal atrophy and intestinal permeability.
Conclusions:
- MTX-induced mucositis involves significant disruption of intestinal proteolysis, particularly lysosomal pathways.
- Increased cathepsin D activity is a key factor in altered mucosal integrity and gut permeability.
- Proteasome regulation may represent an adaptive survival response.
- Targeting proteolytic pathways offers potential therapeutic strategies for mucositis.
More Related Videos
Related Concept Videos
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
Neurokinin 1 (NK1) receptors are distributed across the GI tract, vagal afferents, and key CNS regions including the central vomiting center and chemoreceptor trigger zone (CTZ) Chemotherapy agents stimulate enterochromaffin cells in the gastrointestinal (GI) tract to release large amounts of substance P (SP). SP is a neuropeptide released by specific sensory nerves in response to many different stressors, including those in the GI mucosa affected by chemotherapy. SP binds and activates these...
01:27Chemotherapy-Induced Nausea and Vomiting: 5-HT3 Receptor Antagonists
5-HT3 receptor antagonists, such as dolasetron, granisetron (Kytril), ondansetron (Zofran), and palonosetron (Axoli), are crucial in managing chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea. These drugs selectively block 5-HT3 receptors in the visceral vagal and spinal afferent nerves, chemoreceptor trigger zone, and the vomiting center. They have a rapid onset of action and can be given as a single dose before chemotherapy. Ondansetron and granisetron, in particular,...
01:24Pathophysiology of Peptic Ulcer Disease: Mucosal Defense Factors
Peptic ulcer disease, commonly called PUD, represents a multifaceted condition characterized by disruptions in the lining of the gastrointestinal (GI) tract. Central to the protection of the gastrointestinal lining is the mucosal-bicarbonate barrier. This physiological defense mechanism is a formidable shield against the corrosive effects of gastric acid and pepsin secretion in the stomach. Its role is pivotal in maintaining the structural integrity of the stomach's inner lining. Bicarbonate,...
02:17The Tumor Microenvironment
Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
02:49Cancer Therapies
Cancer therapies are various modes of treatment, such as surgery, radiation therapy, and chemotherapy that are administered to cancer patients.
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...
01:28Peptic Ulcer Disease II: Pathophysiology
Peptic Ulcer Disease (PUD) is characterized by the development of ulcers in the stomach or duodenal mucosa. Its pathophysiology is complex, involving a balance between damaging and protective elements.
Damaging agents such as Helicobacter pylori, gastric acid, pepsin, and nonsteroidal anti-inflammatory drugs (NSAIDs) can weaken the mucosal defense, allowing hydrogen ions to infiltrate back and harm epithelial cells.
Damaging agents such as Helicobacter pylori, gastric acid, pepsin, and nonsteroidal anti-inflammatory drugs (NSAIDs) can weaken the mucosal defense, allowing hydrogen ions to infiltrate back and harm epithelial cells.