Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis

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Abstract

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.

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The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.

Robert F. Furchgott, John Zawadzki (1980)

Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.

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Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007.

Tara Lagu, Michael Rothberg, Meng-Shiou Shieh … (2012)

To assess trends in number of hospitalizations, outcomes, and costs of severe sepsis in the United States. Temporal trends study using the Nationwide Inpatient Sample. Adult patients with severe sepsis (defined as a diagnosis of sepsis and organ dysfunction) diagnosed between 2003 and 2007. We determined the weighted frequency of patients hospitalized with severe sepsis. We calculated age- and sex-adjusted population-based mortality rates for severe sepsis per 100,000 population and also used logistic regression to adjust in-hospital mortality rates for patient characteristics. We calculated inflation-adjusted costs using hospital-specific cost-to-charge ratios. We identified a rapid steady increase in the number of cases of severe sepsis, from 415,280 in 2003 to 711,736 in 2007 (a 71% increase). The total hospital costs for all patients with severe sepsis increased from $15.4 billion in 2003 to $24.3 billion in 2007 (57% increase). The proportion of patients with severe sepsis and only a single organ dysfunction decreased from 51% in 2003 to 45% in 2007 (p < .001), whereas the proportion of patients with three or four or more organ dysfunctions increased 1.19-fold and 1.51-fold, respectively (p < .001). During the same time period, we observed 2% decrease per year in hospital mortality for patients with severe sepsis (p < .001), as well as a slight decrease in the length of stay (9.9 days to 9.2 days; p < .001) and a significant decrease in the geometric mean cost per case of severe sepsis ($20,210 per case in 2003 and $19,330 in 2007; p = .025). The increase in the number of hospitalizations for severe sepsis coupled with declining in-hospital mortality and declining geometric mean cost per case may reflect improvements in care or increases in discharges to skilled nursing facilities; however, these findings more likely represent changes in documentation and hospital coding practices that could bias efforts to conduct national surveillance.

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Role of pulmonary microvascular endothelial cell apoptosis in murine sepsis-induced lung injury in vivo

Sean E. Gill, Marta Rohan, Sanjay Mehta (2015)

Background Sepsis remains a common and serious condition with significant morbidity and mortality due to multiple organ dysfunction, especially acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Sepsis-induced ALI is characterized by injury and dysfunction of the pulmonary microvasculature and pulmonary microvascular endothelial cells (PMVEC), resulting in enhanced pulmonary microvascular sequestration and pulmonary infiltration of polymorphonuclear leukocytes (PMN) as well as disruption of the normal alveolo-capillary permeability barrier with leak of albumin-rich edema fluid into pulmonary interstitium and alveoli. The role of PMVEC death and specifically apoptosis in septic pulmonary microvascular dysfunction in vivo has not been established. Methods In a murine cecal ligation/perforation (CLP) model of sepsis, we quantified and correlated time-dependent changes in pulmonary microvascular Evans blue (EB)-labeled albumin permeability with (1) PMVEC death (propidium iodide [PI]-staining) by both fluorescent intravital videomicroscopy (IVVM) and histology, and (2) PMVEC apoptosis using histologic fluorescent microscopic assessment of a panel of 3 markers: cell surface phosphatidylserine (detected by Annexin V binding), caspase activation (detected by FLIVO labeling), and DNA fragmentation (TUNEL labeling). Results Compared to sham mice, CLP-sepsis resulted in pulmonary microvascular barrier dysfunction, quantified by increased EB-albumin leak, and PMVEC death (PI+ staining) as early as 2 h and more marked by 4 h after CLP. Septic PMVEC also exhibited increased presence of all 3 markers of apoptosis (Annexin V+, FLIVO+, TUNEL+) as early as 30 mins – 1 h after CLP-sepsis, which all similarly increased markedly until 4 h. The time-dependent changes in septic pulmonary microvascular albumin-permeability barrier dysfunction were highly correlated with PMVEC death (PI+; r = 0.976, p < 0.01) and PMVEC apoptosis (FLIVO+; r = 0.991, p < 0.01). Treatment with the pan-caspase inhibitor Q-VD prior to CLP reduced PMVEC death/apoptosis and attenuated septic pulmonary microvascular dysfunction, including both albumin-permeability barrier dysfunction and pulmonary microvascular PMN sequestration (p < 0.05). Septic PMVEC apoptosis and pulmonary microvascular dysfunction were also abrogated following CLP-sepsis in mice deficient in iNOS (Nos2 −/− ) or NADPH oxidase (p47 phox−/− or gp91 phox−/− ) and in wild-type mice treated with the NADPH oxidase inhibitor, apocynin. Conclusions Septic murine pulmonary microvascular dysfunction in vivo is due to PMVEC death, which is mediated through caspase-dependent apoptosis and iNOS/NADPH-oxidase dependent signaling.

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Author and article information

Contributors

Jamie E. Meegan:

ORCID: http://orcid.org/0000-0002-2644-676X

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – review & editing

Ciara M. Shaver: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: VisualizationRole: Writing – review & editing

Nathan D. Putz: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

Jordan J. Jesse: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

Stuart R. Landstreet: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

Han Noo Ri Lee: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

Tatiana N. Sidorova: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

J. Brennan McNeil: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing

James L. Wynn: Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing

Joyce Cheung-Flynn: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing

Padmini Komalavilas: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing

Colleen M. Brophy: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Lorraine B. Ware: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing

Julie A. Bastarache:

ORCID: http://orcid.org/0000-0003-0458-6507

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

You-Yang Zhao: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 3 February 2020

Publication date Collection: 2020

Volume: 15

Issue: 2

Electronic Location Identifier: e0228727

Affiliations

[1 ] Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America

[2 ] Departments of Pediatrics, Pathology, Immunology, and Experimental Medicine, University of Florida Health, Gainesville, FL, United States of America

[3 ] Division of Vascular Surgery, Vanderbilt University Medical Center, Nashville, TN, United States of America

[4 ] Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America

[5 ] Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States of America

Ann and Robert H Lurie Children's Hospital of Chicago, Northwestern University, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: julie.bastarache@ 123456vumc.org

Author information

Jamie E. Meegan http://orcid.org/0000-0002-2644-676X

Julie A. Bastarache http://orcid.org/0000-0003-0458-6507

Article

Publisher ID: PONE-D-19-12903

DOI: 10.1371/journal.pone.0228727

PMC ID: 6996826

PubMed ID: 32012200

SO-VID: 73201e3f-527b-4b1e-baba-0c03dcd02947

License:

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

History

Date received : 14 May 2019

Date accepted : 22 January 2020