# Attenuation of Multiorgan Dysfunction after Shock in the Aged

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $331,800

## Abstract

Abstract
Multiple organ dysfunction is the most common cause of death in injured patients who do not die from brain
injury or uncontrolled hemorrhage. Older patients are at highest risk for morbidity with reduced probability to
return to productive life after trauma and shock. Current therapy is symptomatic without addressing the
underlying mechanisms for the increased morbidity seen in aged individuals. In the past, we advanced the
revolutionary idea that multiorgan dysfunction after trauma/shock is due to leak of the powerful digestive
enzymes across the intestinal mucosal barrier systemically. Specifically, enteral blockade of digestive proteases
in multiple forms of acute shock and sepsis significantly reduces diverse cell dysfunctions, morbidity and
mortality; this intervention is currently being tested in FDA-approved Phase III clinical trial after completion of
multiple successful Phase II studies in cardiac and gastrointestinal surgery patients. In this application we
hypothesize and provide preliminary results that demonstrate chronic escape of digestive enzymes in old
animals from the bowel into systemically, with subsequent infiltration into peripheral organs. Digestive enzymes
cleave extracellular matrix proteins and membrane receptors, causing cell and organ dysfunctions in the old.
When exposed to trauma/shock, the old are subjected to acute leak of digestive enzymes (just like the young)
but in addition, must contend with a chronically accumulated digestive enzyme load in their tissues, leading to
significantly increased multiorgan dysfunction after shock. Our Overall Objective is to use pretreatment of old
rats with inhibitors of digestive enzymes prior to acute trauma/shock to reduce their high level of multiple organ
dysfunction and mortality. Our Specific Aims are to
(1) determine the accumulation and activities of digestive enzymes in tissues outside the gastrointestinal tract of
old versus young rats of both genders. Preliminary results indicate that aged animals have significantly increased
levels of digestive enzymes in peripheral tissues and consequently reduced organ function.
(2) measure the protease activity and organ dysfunction in the old after treatment with digestive enzyme
inhibitors. Our rationale is that one-week blockade of digestive enzymes with competitive inhibitors at low level
(µM) reduces their activity in tissues outside the intestine and improves cell and organ function without
significantly affecting digestive enzyme activity and digestion inside the small intestine (at mM concentrations).
(3) determine multiorgan dysfunction and mortality after trauma/shock in pretreated old animals with attenuated
digestive enzyme activity in their tissues outside the intestine.
Our studies will bring to light a new mechanism for development of organ and cell dysfunction in the old that
is translatable to humans. We will determine the first time the accumulation and temporal activity of digestive
enzymes (including, b...

## Key facts

- **NIH application ID:** 10894122
- **Project number:** 5R01AG083015-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ERIK KISTLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $331,800
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894122

## Citation

> US National Institutes of Health, RePORTER application 10894122, Attenuation of Multiorgan Dysfunction after Shock in the Aged (5R01AG083015-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10894122. Licensed CC0.

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