Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine - Critical Care Research
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Research Overview

Critical Care Research

Pain and Neurosciences Research

Biomedical Innovation

Ethics and Health Policy

Clinical Research

Grant Funding

 
 

Respiratory Critical Care Research Unit

Summary Science Features

The focus of our laboratory's research program has been to elucidate the mechanisms responsible for the cardiovascular dysfunction associated with critical illness and to develop novel therapeutic approaches.

SIRS is often encountered during sepsis and the perioperative period, such as after cardiac surgery requiring cardiopulmonary bypass. It has also been postulated that in humans, SIRS occurs after resuscitation and is related to the poor outcome of patients experiencing cardiac arrest and cardiopulmonary resuscitation (CA/CPR).10

One of the hallmarks of SIRS is endothelial dysfunction and associated reduction in NO availability. However, the precise role of NO in SIRS-induced organ dysfunction remains incompletely understood. The conventional view that SIRS-induced NOS2 is harmful whereas NOS3 is protective has been challenged. For instance, NOS3 has been suggested to have pro-inflammatory role possibly due to NOS3 uncoupling11 whereas NOS2 may confer protective effects in sepsis.12 A part of this uncertainty may be related to the lack of clear understanding of the down-stream mechanisms. NO is known to exert its effects by cGMP-dependent or -independent mechanisms. However, precise contribution of cGMP-dependent and -independent mechanisms in the pathogenesis of SIRS-induced organ dysfunction is largely unknown, at least in part, due to the lack of tools with sufficient specificity. Another source of the confusion as to the role of NO in SIRS may come from the fact that, in most part, the effects of NO has been studied at systemic level using conventional knockout mice and pharmacological inhibitors but not in a tissue-specific manner. It is possible that NO has distinct effects on different tissues. Accordingly, the overall direction of our research program in the next five years is to dissect the molecular mechanisms of sepsis or CA/CPR-induced organ dysfunction with a focus on the down-stream signaling of NO using a tissue-specific approach.

To elucidate the role of cGMP-dependent signaling in the organ dysfunction associated with SIRS, we will examine the impact of soluble guanylate cyclase (sGC) by studying mice deficient for sGC?1 subunit (sGC?1-/-) and mice with mutated sGC?1 subunit (sGC?1kiki) in collaboration with Dr. Peter Brouckaert of the University of Gent.13 We are also planning to generate tissue-specific sGC?1-deficient mice to characterize the tissue-specific effects of cGMP-dependent signaling. Protein S-nitrosylation has been suggested to be a major mechanism responsible for the cGMP-independent effects of NO.14 To clarify the impact of cGMP-independent NO signaling in SIRS-induced organ dysfunction, in collaboration with Dr. Masao Kaneki's laboratory at Mass General, we plan to examine the role of protein S-nitrosylation on organ function by studying mice with tissue-specific overexpression of S-nitrosoglutathione reductase (GSNOR), an enzyme catalyzes de-nitrosylation of GSNO. Tissue specific effects of cGMP-dependent and ?independent mechanisms on the SIRS-induced organ dysfunction will be examined using in vivo mouse models of sepsis15 or CA/CPR16, as well as in isolated or cultured cell systems. By studying the impact of both sGMP-dependent and ?independent signaling mechanisms in a tissue-specific manner, we anticipate that we will be able to elucidate the precise role of NO-dependent signaling in SIRS. 

In summary, the overall direction of our research program over the next five years is to elucidate the precise role of NO/cGMP pathway in the organ dysfunction associated with critical illness. We will take a comprehensive organ-specific approach integrating in vivo and in vitro techniques using a variety of genetically modified mouse models. By the time this proposal is completed, we expect to have learned the mechanisms responsible for the salutary role of cardiac NOS3 on the outcome of CA/CPR. We expect that these studies will provide important insights into the pathogenesis of the post-resuscitation organ dysfunction, likely leading to novel therapeutic strategies.



 
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Department of Anesthesia,
Critical Care and Pain Medicine
Gray-Bigelow 444
55 Fruit Street
Boston, MA 02114

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