NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome

Whitmore, Laura C.; Goss, Kelli L.; Newell, Elizabeth A.; Hilkin, Brieanna M.; Hook, Jessica S.; Moreland, Jessica G.

doi:10.1152/ajplung.00054.2014

Cited by 25 publications

(25 citation statements)

References 39 publications

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“…An increased inflammatory response in the absence of ROS has also been observed in conditions that are not considered classical autoimmune diseases, for example in zymosan-or monosodium urate crystal-induced inflammation (30,48,49). This indicates that ROS also regulates T cell-independent inflammatory pathways.…”

Section: Discussionmentioning

confidence: 86%

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

et al. 2017

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Section: Discussionmentioning

confidence: 86%

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

et al. 2017

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“…Our laboratory became interested in neutrophil responses to TLR2 agonists after finding complex and unexpected interactions between TLR2 ligation and the NADPH oxidase 2 using a murine model of systemic inflammation elicited by injection of a TLR2 agonist (15, 16). In the current study, we sought to further define human PMN priming responses to TLR2 ligands in vitro/ex vivo .…”

Section: Introductionmentioning

confidence: 99%

A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

Whitmore

Hook

Philiph

et al. 2016

The Journal of Immunology

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Polymorphonuclear leukocytes (PMN) achieve an intermediate or “primed” state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage in certain disease contexts including sepsis. As PMN priming by TLR4 agonists is well-described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly, PMN from only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species (ROS), MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1, and were demonstrated to have enhanced association of TLR1 with the ER chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit (PICU) length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer PICU stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.

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“…Here we investigated the effect of Galactomannan (GM), a polysaccharide derived from Aspergillus fumigatus cell wall, and Zymosan (Zym) a cell-wall extract of Saccharomyces cerevisiae [ 17 ] on ciliary clearing mechanism. Both GM and Zym stimulate innate immune responses [ 18 ], however their effects onto the function of adrenaline activated tracheal ciliary epithelial cells is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium

et al. 2015

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BackgroundCiliary beating by respiratory epithelial cells continuously purges pathogens from the lower airways. Here we investigated the effect of the fungal cell wall polysaccharides Galactomannan (GM) and Zymosan (Zym) on the adrenergic activated particle transport velocity (PTV) of tracheal epithelium.MethodsExperiments were performed using tracheae isolated from male C57BL/6J mice. Transport velocity of the cilia bearing epithelial cells was measured by analysing recorded image sequences. Generation of reactive oxygen species (ROS) were determined using Amplex Red reagents. PCR experiments were performed on isolated tracheal epithelium to identify adrenergic receptor mRNA.ResultsThe adrenergic receptors α1D, α2A, β1 and β2 have been identified in isolated tracheal epithelium. We found epinephrine responsible for an increase in PTV, which could only be reduced by selective β-receptor-inhibition. In addition, either GM or Zym prevented the epinephrine induced PTV increase. Furthermore, we observed a strong ROS generation evoked by GM or Zym. However, epinephrine induced increase in PTV recovered in the presence of GM and Zym after application of ROS scavengers.ConclusionBoth GM or Zym trigger reversible ROS generation in tracheal tissue leading to inhibition of the β-adrenergic increase in PTV.

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NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome

Cited by 25 publications

References 39 publications

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps

A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium

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