Myeloperoxidase Deficiency Attenuates Lipopolysaccharide-Induced Acute Lung Inflammation and Subsequent Cytokine and Chemokine Production

Haegens, Astrid; Heeringa, Peter; Suylen, Robert Jan van; Steele, Chad; Aratani, Yasuaki; O’Donoghue, Robert J.J.; Mutsaers, Steven E.; Mossman, Brooke T.; Wouters, Emiel F.M.; Vernooy, Juanita H. J.

doi:10.4049/jimmunol.0800377

Cited by 103 publications

(94 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In agreement with this finding, others have reported that neutrophils from MPOdeficient mice express higher levels of IL-10 in response to LPS than those of cells isolated from wild-type mice (28). Furthermore, we previously described that hLF1-11 enhanced the mRNA expression of IL-10 and the NF-kB activation and translocation in LPS-stimulated monocytes (18).…”

Section: Discussionsupporting

confidence: 76%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte–macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity.

show abstract

Section: Discussionsupporting

confidence: 76%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The intratracheal instillation of LPS in mice or rats is an established model of acute pulmonary inflammation (19,22), and is known to involve the NF-kB activation of resident as well as infiltrating immune cells (23,24). In line with these observations, elevated NF-kB transcriptional activity and increased concentrations of transcripts encoding inflammatory and NF-kB-responsive genes were detected in lung homogenates of intratracheal LPS-treated animals.…”

Section: Discussionsupporting

confidence: 71%

“…All studies were performed according to a protocol approved by the Institutional Animal Care Committee of Maastricht University. Acute lung inflammation was induced in anesthetized mice by the intratracheal instillation of 20 mg LPS (Escherichia coli, serotype O55:B5; Sigma, St. Louis, MO) dissolved in 50 ml sterile 0.9% NaCl, as described previously (19). In some experiments, animals were pair-fed to match the 24-hour food intake by intratracheal NaCl-treated or intratracheal LPS-treated mice.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were killed 4, 7, 24, 48, 72, 96, or 120 hours after LPS instillation, and a heart puncture was performed to collect blood for leukocyte isolation (as will be described) or to obtain plasma. Lungs were processed to assess local inflammation, as described previously (19). The soleus, gastrocnemius, tibialis anterior, and plantaris muscles were collected from both hind limbs, using standardized dissection methods.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

NF-κB Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

Langen¹,

Haegens²,

Vernooy³

et al. 2012

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Disease exacerbations and muscle wasting comprise negative prognostic factors of chronic obstructive pulmonary disease (COPD). Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting after acute exacerbations of COPD. However, the interactions between systemic inflammation and malnutrition in their contributions to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy, remain unresolved. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS to model acute disease exacerbation. Systemic inflammation, nutritional intake, and body and muscle weights were determined. Muscle inflammatory signaling and atrophy signaling were examined, and the effect of the muscle-specific inactivation of NF-kB on muscle atrophy was assessed in genetically modified mice. The intratracheal LPS instillation was followed by markedly elevated circulating cytokine concentrations and NF-kB activation in extrapulmonary tissues, including skeletal muscle. The administration of intratracheal LPS increased the expression of muscle E3 ubiquitin ligases, which govern muscle proteolysis, in particular MuRF1, and caused a rapid loss of muscle mass. Reduced food intake only partly accounted for the observed muscle atrophy, and did not activate NF-kB in muscle. Rather, plasma transfer experiments revealed the presence of NF-kB-signaling and atrophy-signaling properties in the circulation of intratracheal LPStreated mice. The genetic inhibition of muscle NF-kB activity suppressed intratracheal LPS-induced MuRF1 expression and resulted in a significant sparing of muscle tissue. Systemic inflammation and malnutrition contribute to the muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-kB activation is required for the transition from inflammatory to muscle atrophy signaling.Keywords: pulmonary inflammation; systemic inflammation; muscle atrophy; NF-kB; cytokines Acute exacerbations of chronic obstructive pulmonary disease (COPD) are accompanied by pulmonary and transient systemic inflammation and malnutrition, which have been implicated in the onset of stepwise weight loss, muscle wasting and increased mortality (1-6). The underlying mechanisms are unknown and difficult to unravel in patients during the acute phase of an exacerbation. In many instances, the acute loss of muscle mass is dependent on increased muscle protein breakdown mediated by the ubiquitin (Ub) 26S-proteasome system (UPS) (7). The rate-limiting enzymes of this process during acute muscle atrophy include the Ub-E3 ligation enzymes atrogin-1/MAFbx and MuRF1. The genetic deletion of these "atrogenes" attenuates muscle atrophy under various conditions (8, 9), and the increased expression of MuRF1 and atrogin-1 has been reported in quadriceps muscle during exacerbations of COPD (1). Inducible transcription factors, including NF-kB, have been implicated in the transcriptional regulation of atrogin-1 and MuRF1 (10). NF-k...

show abstract

“…This method allows study of the effect and/or role of the material administered on the physiology and/or pathology of lung. The materials administered can be endogenous molecules such as cytokines, or exogenous materials such as xenobiotic chemicals/drugs, carcinogens, pollutants, allergens, or viruses that result in various lung conditions that may represent a model for studying various human diseases [6][7][8][9][10] . This technique can also be used in conjunction with recombinant adenovirus or lentivirus to introduce overexpression or deletion of genes of interest in airway epithelial cells to study the role of these genes in homeostasis, physiology, pathology, and/or carcinogenesis of lung.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Intratracheal Intubation to Study the Pathology and Physiology of Mouse Lung

Cai

Kimura

2013

JoVE

View full text Add to dashboard Cite

The use of a model that mimics the condition of lung diseases in humans is critical for studying the pathophysiology and/or etiology of a particular disease and for developing therapeutic intervention. With the increasing availability of knockout and transgenic derivatives, together with a vast amount of genetic information, mice provide one of the best models to study the molecular mechanisms underlying the pathology and physiology of lung diseases. Inhalation, intranasal instillation, intratracheal instillation, and intratracheal intubation are the most widely used techniques by a number of investigators to administer materials of interest to mouse lungs. There are pros and cons for each technique depending on the goals of a study. Here a noninvasive intratracheal intubation method that can directly deliver exogenous materials to mouse lungs is presented. This technique was applied to administer bleomycin to mouse lungs as a model to study pulmonary fibrosis. Video LinkThe video component of this article can be found at

show abstract

Myeloperoxidase Deficiency Attenuates Lipopolysaccharide-Induced Acute Lung Inflammation and Subsequent Cytokine and Chemokine Production

Cited by 103 publications

References 16 publications

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

NF-κB Activation Is Required for the Transition of Pulmonary Inflammation to Muscle Atrophy

Noninvasive Intratracheal Intubation to Study the Pathology and Physiology of Mouse Lung

Contact Info

Product

Resources

About