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New Preclinical Research Models Could Lead to Better Diagnosis, Treatment of Sepsis and ARDS

Novel large animal research models developed at the University of Michigan Center for Integrative Research in Critical Care fill a crucial gap in the translational study of life-threatening critical illness and injury.

Foreground (from left): Research Laboratory Technician Anne Marie Weitzel
Foreground (from left): Research Laboratory Technician Anne Marie Weitzel; PC3L Associate Director Brendan McCracken, MS; and PC3L Director Hakam Tiba, MD, MS. Background: Research Laboratory Technician Carmen Colmenero, BS.

The Pre-Clinical Critical Care Laboratory (PC3L) team at the Michigan Center for Integrative Research in Critical Care (MCIRCC) has developed two new models of infection and lung injury to further understand the underlying mechanisms of infection-induced multi-organ dysfunction and failure, a major step forward in the improvement of research and treatment for illnesses like sepsis and the Acute Respiratory Distress Syndrome (ARDS).

The research team, led by Dr. Hakam Tiba, Assistant Research Professor of Emergency Medicine and Director of the PC3L, piloted a novel large animal study of infection to create a clinically relevant and reproducible model that mimics the human condition of sepsis, circumventing a significant obstacle in previous research.

“The importance of this model is its clinical relevance,” said Tiba. “It recapitulates the clinical state of severe infection in patients — how an infection would develop and how it would progress into multi-organ failure over time.”

Despite its enormous impact on human health — over 48.9 million cases globally per year with 1.7 million in the U.S. alone — sepsis remains ill-defined with little progress made to further understand its pathogenesis or to find effective diagnostics or therapies. One of the major obstacles to advancing knowledge of this disease is the absence of translatable preclinical models that accurately illustrate the evolution of systemic responses to infection in humans.

Published in PLOS ONE in December of 2020, the authors presented a pilot study using a swine model of untreated kidney infection and systemic inflammation that demonstrates the physiologic and immunologic features associated with development of human sepsis, using the kidney as the infection source. The approach is envisioned to lead to the development of more clinically relevant models that would further allow the assessment of responses to a variety of treatment scenarios.

“There have been decades of research in sepsis that have relied on small animal models that have failed to translate into anything clinically relevant,” said Brendan McCracken, Associate Director of PC3L. “While rodent models are often a valid means of studying numerous basic science mechanisms, there is a big need in the research community to find a model that more closely replicates what is being seen in the clinics.”

In May of this year, the team furthered this point in a second paper published in Physiological Reports which described a study funded by The Michigan Institute for Clinical & Health Research (MICHR) that used the sepsis model with the addition of clinically relevant lung injury exposures to induce ARDS, a life‐threatening lung condition that affects more than 200,000 people in the United States each year.

“Building a clinically faithful ARDS model is somehow predicated on a preexisting condition,” said McCracken. “This study is a multi-layered model that has not been used before. The model mimics an untreated kidney infection as an underlying condition uniquely followed by a clinically relevant lung injury on top of that. This strategy has not been well documented in other pre-clinical research.”

As a controlled large animal model, this study addresses some important preclinical gaps in the study of ARDS left by the vast majority of experimental research that has been performed using rodents. To address these gaps, the team designed the swine model using clinically relevant exposures that (1) faithfully reiterate the physiologic, radiographic, and histopathologic features of human ARDS, (2) allow for longitudinal study of pathogenesis, underlying mechanisms, and treatment strategies, and (3) permit study of co‐interventions and organ support (e.g., vasopressors and mechanical ventilation).

“These models do a much better job of modeling the human condition than the most commonly used models in mice,” said Dr. Robert Dickson, Associate Professor, Pulmonary & Critical Care, Microbiology & Immunology, MCIRCC Associate Director, and co-author on the studies. “Our ARDS model recapitulates all of the physiologic, radiographic, and pathologic features of what we see in humans with severe lung injury. This fidelity to human disease is exactly what the field needs in terms of a useful pre-clinical model.”

The team is already thinking about future therapeutic, diagnostic, and mechanistic studies that can be done utilizing this model moving forward. They have submitted multiple grants to study the microbiome-metabolome interface and its impact on the development and severity of ARDS, and are eager to identify biomarkers of disease progression and therapeutic response.

“The MCIRCC preclinical lab is uniquely stationed and positioned to handle models like this,” said Tiba. “Our resources and our experience made this project possible, and now that we have the model established, we can build on it.” MCIRCC’s PC3L also has high fidelity large animal models of cardiac arrest, traumatic brain injury, and polytrauma.

Dr. Kathleen Stringer, Professor of Clinical Pharmacy, MCIRCC Associate Director and co-author on the sepsis and ARDS papers sees a bright future for this research. “These models will permit the identification of mechanistically grounded therapeutic targets and more reliable testing and translation of candidate pharmacotherapy,” she said. “This could bring about a paradigm change for targeted therapies for the effective treatment of both sepsis and ARDS.”

A comprehensive assessment of multi-system responses to a renal inoculation of uropathogenic E. coli in swine. Mohamad Hakam Tiba, Brendan M. McCracken, Robert P. Dickson, Jean A. Nemzek, Carmen I. Colmenero, Danielle C. Leander, Thomas L. Flott, Rodney C. Daniels, Kristine E. Konopka, J. Scott VanEpps, Kathleen A. Stringer, Kevin R. Ward. Published: December 11, 2020.

A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures. Mohamad H. Tiba, Brendan M. McCracken, Danielle C. Leander, Carmen I. Colmenero, Jean A. Nemzek, Michael W. Sjoding, Kristine E. Konopka, Thomas L. Flott, J. Scott VanEpps, Kathleen A. Stringer, Robert P. Dickson. First published: 15 May 2021.

This story was originally published by the Michigan Center for Integrative Research in Critical Care (MCIRCC) on June 11, 2021.

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