Neutrophil FFA2/GPR43 Receptor Expression in Patients With the Diagnosis of Sepsis (GPR43Sepsis)

January 11, 2017 updated by: Zyad J. Carr, M.D., Milton S. Hershey Medical Center

This study seeks to elucidate the quantitative expression of G - protein receptor 43/free fatty acid (GPR43/FFA2) receptors in patients with the diagnosis of sepsis and specifically, its expression as it relates to the severity of sepsis. The investigators hypothesize that patients with more severe sepsis, as defined by a higher SOFA (Sequential Organ Failure Assessment Score), will have decreased expression of the GPR43/FFA2 as compared to patients with lower SOFA scores, consistent with a less exuberant immune response to infection.

Patients admitted to Penn State Hershey Medical Center with a diagnosis of sepsis of any cause will undergo blood testing of leukocytes to determine the expressed quantity of GP43 during standardized time points of their illness and recovery. No interventions will be made in the standard clinical management of the patient. Additionally, healthy volunteers will be recruited to exam baseline GPR43 receptor expression between sepsis and control groups.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Despite advancements in recognition and treatment, sepsis continues to be a frequently fatal condition comprising 750,000 cases in the US with an estimated death rate of 28-38%. Bacterial sepsis complications are the result of a cascade of inflammatory mediators secondary to the immune system's recognition and response to invading bacteria, intracellular constituents and metabolites. Bacterial recognition results in the widespread activation of biological mediators essential to the immune response such as cytokines, chemokines, prostaglandins and reactive oxygen species. These compounds result in the activation and up-regulation of neutrophils, monocytes at the cellular level as well as the physiological changes of sepsis such as hyperpyrexia, vasodilation, and tachycardia. Despite this generally coordinated response, it is likely that marked complications are related to the sequela of the uncontrolled immune response leading to significant injury to the lungs (Acute Respiratory Distress Syndrome), and other organs (acute renal failure, shock liver). In addition, there is question that impairment of the gut mucosal barrier may result in translocation of bacteria and perpetuate the multiple organ failure.

G protein-coupled receptors (GPCRs) comprise one of the largest collections of transmembrane proteins in the mammalian genome. Recently, a subfamily of G protein coupled receptors have been identified that utilize short chain free fatty acids as ligands, FFA1 (GPR40), FFA2 (GPR43) and FFA3 (GPR41). Research has intimated that these receptors are involved in essential biological crosstalk between colonic bacteria, host and immune defenses. Although highly conserved in structure, members of this sub family demonstrate differences in fatty acid specificity, intracellular signaling mechanisms and tissue localization. Specifically, FFA2 (GPR43)4 expression has been shown to be expressed in higher magnitudes within immune cells, has been hypothesized to be involved in the modulation of pro- and anti-inflammatory mediators, such as prostaglandin E2 and is involved in neutrophil chemotaxis in mice. GPR43 is involved in the process of differentiation of progenitor immune cells into monocytes and macrophages, a key component of host defense. In addition, highly selective expression of GPR43 in polymorphonuclear cells point to strong role in chemotaxis and recruitment of immune cells to foci of bacterial infection. Short chain fatty acids also activate GPR43 receptors on intestinal epithelial cells with rapid production of secondary chemokine and cytokines after being challenged with inflammation and infection, and likely aid in the coordinated immune response. GP43 is likely an essential component of the phagocytic chemotaxis that maintains normal intestinal immune defense. In a model of acute colitis, GPR43 knockout mice demonstrated increased mortality. The authors concluded that GPR43 deficiency likely suppressed the role of immune cells within the gut immune milieu leading to death from sepsis related complications. Conversely, in a chronic colitis model, GPR43 deficient knockout mice demonstrated reduced colonic inflammation, without overwhelming infection, the authors concluded that GPR43 has an unfavorable role in the manifestation of chronic inflammatory conditions. These findings were confirmed with at least one later study. In humans, fetal membrane expression of GPR43 was higher in parturients in preterm labor with signs of infection.

Study Type

Observational

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Adult patients with the diagnosis of sepsis or septic shock admitted to the intensive care unit at Penn State Hershey Medical Center, Hershey PA 17033.

Description

Inclusion Criteria:

  • Diagnosis of sepsis or septic shock
  • Age greater than eighteen years old.
  • Ability to give informed consent (as determined by the attending physician) or presence of designated healthcare proxy that can give informed consent.

Exclusion Criteria:

  • Patients or designated healthcare proxy with the inability to give informed consent.
  • Patients under the age of eighteen

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Sepsis
Patients with the diagnosis of sepsis or septic shock
Other: phlebotomy
phlebotomy
Control
Healthy control with no evidence of active infection, or recent infection in the past 4 weeks.
Other: phlebotomy
phlebotomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantitative FFA2/GPR43 receptor expression as a function of SOFA score
Time Frame: Time of diagnosis, 24, 72, 168 hour intervals
Quantitative expression of FFA2/GPR43 will be measured at specific time intervals and compared to SOFA score.
Time of diagnosis, 24, 72, 168 hour intervals

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Milton S. Hershey Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2016

Primary Completion (Anticipated)

August 1, 2017

Study Completion (Anticipated)

November 1, 2017

Study Registration Dates

First Submitted

March 1, 2016

First Submitted That Met QC Criteria

March 1, 2016

First Posted (Estimate)

March 7, 2016

Study Record Updates

Last Update Posted (Estimate)

January 13, 2017

Last Update Submitted That Met QC Criteria

January 11, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00004607

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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