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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Neutrophil FFA2/GPR43 Receptor Expression in Patients With the Diagnosis of Sepsis

Conditions
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Sepsis, Septic Shock, Multiple Organ Dysfunction, Intra-abdominal Sepsis

Intervention / Treatment
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* Other: phlebotomy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sepsis<br>Patients with the diagnosis of sepsis or septic shock | Other: phlebotomy<br>* phlebotomy<br>|
| Control<br>Healthy control with no evidence of active infection, or recent infection in the past 4 weeks. | Other: phlebotomy<br>* phlebotomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative FFA2/GPR43 receptor expression as a function of SOFA score | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Septic Shock, Multiple Organ Dysfunction, FFA2, GPR43