Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome

Meyer, Nuala J.; Reilly, John P.; Feng, Rui; Christie, Jason D.; Hazen, Stanley L.; Albert, Carolyn J.; Franke, Jacob D.; Hartman, Celine L.; McHowat, Jane; Ford, David A.

doi:10.1172/jci.insight.96432

Cited by 38 publications

(68 citation statements)

References 77 publications

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“…In patients, elevated circulating MPO levels were associated with small vessel-related stroke risk [37]. The Ford group has previously reported that 2-chloro FA formed via HOCl-mediated attack of plasmalogens contribute to pulmonary endothelial injury and have prognostic utility in sepsis-associated acute respiratory distress syndrome [38]. Therefore, the pharmacological benefit for MPO in preclinical settings of neurological disease models including inflammation-induced BBB dysfunction is following the 'inhibit ROS toxifiers' concept.…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

Goeritzer

Bernhart

Plastira

et al. 2020

IJMS

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During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO−/− compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction.

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Section: Discussionmentioning

confidence: 99%

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

Goeritzer

Bernhart

Plastira

et al. 2020

IJMS

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“…Person exposed to Cl 2 gas also had elevated plasma levels of 16-carbon chlorinated fatty acid (ClFA) ( Figure 1B) and 18-carbon ClFA ( Figure 1C), as measured in plasma obtained from these individuals 3-6 h post exposure in the emergency room. These values were about 20 fold higher than those found in patients with sepsis (28). Similarly, exposure of adult C57BL/6 male mice to Cl 2 gas (400ppm, 30 min) increased plasma levels of CFH levels Adult male C57BL/6 mice were exposed to Br 2 gas (600ppm, 30min) and returned to room air.…”

Section: Resultsmentioning

confidence: 72%

“…Using LC/MS quantitation, we found that the plasma levels of 16-carbon (Figure 2A-C) and 18-carbon ( Figure 2D-F) free-and esterified-brominated fatty acids (BrFA) were elevated in the exposed animals. Even at 24 hours post exposure, the values of these variables were higher than those measured in patients with ARDS (28). We also identified elevated levels of brominated fatty aldehyde (BrFALD) in the broncholaveolar lavage fluid (BALF) (Supplementary Figure 1A, E) of exposed animals.…”

Section: Halogenated Lipids Increase Rbc Hemolysis and Cell-free Hemementioning

confidence: 76%

“…Interestingly, we found that ClFA were also elevated in humans that were accidently exposed to Cl 2 gas suggesting that halogenated lipids may be responsible for hemolysis post inhalation of toxic gases. Moreover, recent studies have shown that these halogenated lipids are elevated in patients who have ARDS secondary to sepsis and correlate with the disease severity (28). In these patients, chlorinated and brominated lipids are increased as an end product of reactions by myeloperoxidase (MPO) and eosinophil peroxidase (EPO) respectively (43).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that exposure to Br 2 (600ppm, 30min) or Cl 2 (400ppm, 30min) causes lung pathology similar to ARDS (9,(25)(26)(27) and that this injury is mediated at least in part by halogenated lipids, formed by the interaction of halogen gases with plasmalogens on the surface of lung epithelial cells, which are released into the alveolar spaces and plasma. Recent studies have shown that these halogenated lipids are elevated in patients who have ARDS (28) secondary to sepsis and also correlate with the disease severity (28).…”

Section: Introductionmentioning

confidence: 99%

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Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

Aggarwal

Lazrak

Ahmad

et al. 2020

Preprint

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Fax: (205) 934-7476; Tel: (205) 975-9673 Conflict of interest statement: The authors have declared that no conflict of interest exists.Authors Contribution: SA and IA designed and performed studies assessing RBC lysis measurements of heme and heme induced oxidative injury; AL and ZY designed and performed the ion transport experiments; JAM designed, conducted and analyzed the mass spectrometry studies; AB, DF and SM completed the necessary forms to obtain permissions from the UAB and St. Louis University IRBs to perform measurements in human samples; DAF designed and performed all measurements to assess brominated lipids in humans and mice; SA performed the modelling studies; SA, AL and SM wrote all drafts of this manuscript; SM conceived the study, designed and organized experiments, analyzed data, and inspected all primary data. ABSTRACTWe previously reported that cell-free heme (CFH) is increased in the plasma of patients with acute and chronic lung injury and causes pulmonary edema in animal model of acute respiratory distress syndrome (ARDS) post inhalation of halogen gas. However, the mechanisms by which CFH causes pulmonary edema are unclear. Herein we report for the first time the presence of CFH and chlorinated lipids (formed by the interaction of halogen gas, Cl 2 , with plasmalogens) in the plasma of patients and mice exposed to Cl 2 gas. Ex vivo incubation of red blood cells (RBC) with halogenated lipids caused oxidative damage to RBC cytoskeletal protein spectrin, resulting in hemolysis and release of CFH. A single intramuscular injection of the heme-scavenging protein hemopexin (4 µg/kg body weight) in mice, one hour post halogen exposure, reversed RBC fragility and decreased CFH levels to those of air controls. Patch clamp and short circuit current measurements revealed that CFH inhibited the activity of amiloridesensitive (ENaC) and cation sodium (Na + ) channels in mouse alveolar cells and transepithelial Na + transport across human airway cells with EC 50 of 125 nM and 500 nM, respectively. Molecular modeling identified 22 putative heme-docking sites on ENaC (energy of binding range: 86-1563 kJ/mol) with at least 2 sites within its narrow transmembrane pore, potentially capable of blocking Na + transport across the channel. In conclusion, results suggested that CFH mediated inhibition of ENaC activity may be responsible for pulmonary edema post inhalation injury.

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Ferulic acid alleviates lipopolysaccharide‐induced acute lung injury through inhibiting TLR4/NF‐κB signaling pathway

Lin

2020

J Biochem & Molecular Tox

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Ferulic acid (FA) exhibits anti‐inflammatory, antidiabetic, antihyperlipidemic, antioxidant, neuroprotective, and antihypertensive effects. This study aimed to determine whether FA could ameliorate lipopolysaccharide (LPS)‐induced inflammatory responses and acute lung injury (ALI) in mice. Mice were challenged with LPS intratracheally to induce ALI 1 h after 3 days of FA (25, 50, and 100 mg/kg) or dexamethasone (DEX; 5 mg/kg) administration. The lung tissues and bronchoalveolar lavage fluid (BALF) were collected 12 h after the LPS challenge. Pretreatment with FA or DEX could attenuate lung histopathological change, complement deposition, and lung wet‐to‐dry weight ratio of mice injured by LPS. Meanwhile, the influx of neutrophils and macrophages, as well as the production of proinflammatory cytokine (tumor necrosis factor‐alpha, interleukin 1 beta [IL‐1β], and IL‐6), in BALF of ALI mice was significantly decreased. Moreover, FA or DEX markedly reversed the LPS‐induced elevation of myeloperoxidase activity and monocyte chemoattractant protein‐1 level in lung tissues of ALI mice. In addition, the Western blot analysis demonstrated that FA or DEX effectively inhibited the LPS‐induced activation of the toll‐like receptor 4 (TLR4)/nuclear factor‐kappa B (NF‐κB) signaling pathway in lung tissues. The current study suggested that the alleviating effect of FA against LPS‐induced ALI might be partially due to the inhibition of the inflammatory response via inactivation of the TLR4/NF‐κB signaling pathway.

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Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome

Cited by 38 publications

References 77 publications

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

Heme Impairs Alveolar Epithelial Sodium Channels Post Toxic Gas Inhalation

Ferulic acid alleviates lipopolysaccharide‐induced acute lung injury through inhibiting TLR4/NF‐κB signaling pathway

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