an-intact-pericardium-ischemic-rodent-model

An Intact Pericardium Ischemic Rodent Model

This protocol has shown that the pericardium and its contents play an essential anti-fibrotic role in the ischemic rodent model (coronary ligation to ...

Cumming School of Medicine

University of Calgary

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is reaching epidemic proportions causing morbidity, mortality, and chronic disease due to relapses, suggesting an intracellular reservoir. Using spinning-disk confocal intravital microscopy to track MRSA-GFP in vivo, we identified that within minutes after intravenous infection MRSA is primarily sequestered and killed by intravascular Kupffer cells (KCs) in the liver. However, a minority of the Staphylococci overcome the KC's antimicrobial defenses. These bacteria survive and proliferate for many days within this intracellular niche, where they remain undetected by recruited neutrophils. Over time, the KCs lyse, releasing bacteria into the circulation, enabling dissemination to other organs such as the kidneys. Vancomycin, the antibiotic of choice to treat MRSA bacteremia, could not penetrate the KCs to eradicate intracellular MRSA. However, based on the intravascular location of these specific macrophages, we designed a liposomal formulation of vancomycin that is efficiently taken up by KCs and diminished the intracellular MRSA. Targeting the source of the reservoir dramatically protected the liver but also dissemination to other organs, and prevented mortality. This vancomycin formulation strategy could help treat patients with Staphylococcal bacteremia without a need for novel antibiotics by targeting the previously inaccessible intracellular reservoir in KCs.

Identification and treatment of the Staphylococcus aureus reservoir in vivo.

Monocytes are circulating leukocytes important in both innate and adaptive immunity, primarily functioning in immune defense, inflammation, and tissue remodeling. There are 2 subsets of monocytes in mice (3 subsets in humans) that are mobilized from the bone marrow and recruited to sites of inflammation, where they carry out their respective functions in promoting inflammation or facilitating tissue repair. Our understanding of the fate of these monocyte subsets at the site of inflammation is constantly evolving. This brief review highlights the plasticity of monocyte subsets and their conversion during inflammation and injury.

Monocyte Conversion During Inflammation and Injury.

Neutrophils are key components of the innate immune system that play important roles during infection, injury, and chronic disease. In recent years, neutrophil heterogeneity has become an emerging focus with accumulating evidence of neutrophil populations with distinct functions under both steady-state and pathologic conditions. Despite these advances, it remains unclear whether these different populations represent bona fide subsets or simply activation/polarization states in response to local cues. In this review, we summarize the varied neutrophils populations that have been described under both basal and during inflammation. We discuss the evidence that supports the existence of neutrophils subsets. Finally, we identify potential gaps in our knowledge that may further advance our current understanding of neutrophil heterogeneity.

Neutrophil heterogeneity: Bona fide subsets or polarization states?

Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6 macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6 macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium.

Gata6 Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis.

The pericardium is a double-layered fibro-serous sac that envelops the majority of the surface of the heart as well as the great vessels. Pericardial fluid is also contained within the pericardial space. Together, the pericardium and pericardial fluid contribute to a homeostatic environment that facilitates normal cardiac function. Different diseases and procedural interventions may disrupt this homeostatic space causing an imbalance in the composition of immune mediators or by mechanical stress. Inflammatory cells, cytokines, and chemokines are present in the pericardial space. How these specific mediators contribute to different diseases is the subject of debate and research. With the advent of highly specialized assays that can identify and quantify various mediators we can potentially establish specific and sensitive biomarkers that can be used to differentiate pathologies, and aid clinicians in improving clinical outcomes for patients.

An overview of human pericardial space and pericardial fluid.

Post-operative adhesions affect patients undergoing all types of surgeries. They are associated with serious complications, including higher risk of morbidity and mortality. Given increased hospitalization, longer operative times, and longer length of hospital stay, post-surgical adhesions also pose a great financial burden. Although our knowledge of some of the underlying mechanisms driving adhesion formation has significantly improved over the past two decades, literature has yet to fully explain the pathogenesis and etiology of post-surgical adhesions. As a result, finding an ideal preventative strategy and leveraging appropriate tissue engineering strategies has proven to be difficult. Different products have been developed and enjoyed various levels of success along the translational tissue engineering research spectrum, but their clinical translation has been limited. Herein, we comprehensively review the agents and products that have been developed to mitigate post-operative adhesion formation. We also assess emerging strategies that aid in facilitating precision and personalized medicine to improve outcomes for patients and our healthcare system.

Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies.

Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.

Article	Year
Identification and treatment of the Staphylococcus aureus reservoir in vivo. The Journal of experimental medicine\| PubMed ID: 27325887	2016
Monocyte Conversion During Inflammation and Injury. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 27765768	2017
Neutrophil heterogeneity: Bona fide subsets or polarization states? Journal of leukocyte biology\| PubMed ID: 29462505	2018
Gata6 Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis. Immunity\| PubMed ID: 31315031	2019
An overview of human pericardial space and pericardial fluid. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology\| PubMed ID: 34023529	2021
Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies. Biomolecules\| PubMed ID: 34356652	2021
Post-Operative Adhesions: A Comprehensive Review of Mechanisms. Biomedicines\| PubMed ID: 34440071	2021

Justin F. Deniset

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