# Sepsis and the benefits of permissive hypoxia

> **NIH NIH K08** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $193,860

## Abstract

PROJECT SUMMARY / ABSTRACT
This project proposes a five-year research career development program focused on the study of permissive
hypoxia in sepsis to expand the depth and breadth of understanding of the underlying mechanisms of
mitochondrial dysfunction in this milieu. Currently, oxygen administration is the most widely administered drug
in in-hospital care, and is liberally titrated to avoid potentially injurious periods of hypoxemia. Mounting
evidence in several allied species suggest that not only is hyperoxia detrimental, but that local tissue hypoxia
may in fact be beneficial to an evolved, requisite, and protective biological process. In critical illness such as
sepsis, mitochondrial dysfunction is common, due in large part to oxidative stress, that results in impaired ATP
generation, mitophagy, and in some cases, cell death. Strategies to mitigate or ameliorate this dysfunction and
promote decreases in morbidity and mortality are therefore sought. Delivery of exogenously delivered carbon
monoxide (CO) has stood out as a promising strategy because of its ability to simulate a protective hypoxic
pathway. CO is generated endogenously by heme oxygenase-1 (HO-1) as part of the stress response. These
molecules are potently salutary in models of sepsis and tissue hypoxia. Mechanistically, mitochondria are
principal targets for these bioactive gases, with both oxygen and CO competing for binding to the large number
of hemoproteins within the matrices. Using established models of bacterial sepsis in mice involving cecal
ligation and puncture, this project will evaluate the role of HO-1/CO in mitigating mitochondrial dysfunction
through modulation of inflammation. We will study the neutrophil where preliminary data suggest that these
cells are influenced by CO. These models will be used to characterize the host response to sepsis and how
oxygen titration affects mitochondrial function and survival. We will assess changes in mitochondrial function
and protein glycosylation signatures linked to metabolsism known to be altered during hypoxia, investigate how
mitochondria in the neutrophil are influenced by oxygen, and evaluate HO-1 and CO in promoting effective and
appropriate bacterial clearance and resolution of inflammation.
Guided by strong mentorship with significant expertise, this work has the opportunity to transcend observations
around oxygen titration in the perioperative and critical care settings. Further, this project includes a well-
structured and rigorous career development plan to build upon the candidates strong clinical and preclinical
experience. Combined with an extraordinary environment and institutional support, the successful completion
of the proposed project will provide the candidate with the skills and experience necessary to successfully
compete for funding as an independent clinician scientist, with translational expertise in an innovative research
niche.

## Key facts

- **NIH application ID:** 10450186
- **Project number:** 5K08GM134220-04
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Shahzad Shaefi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $193,860
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450186

## Citation

> US National Institutes of Health, RePORTER application 10450186, Sepsis and the benefits of permissive hypoxia (5K08GM134220-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450186. Licensed CC0.

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