Kinetics of pulmonary neutrophil recruitment and clearance in a natural and spontaneously resolving model of airway inflammation

Brazil, Timothy J.; Dagleish, Mark P.; McGorum, Bruce; Dixon, Padraic; Haslett, Christopher; Chilvers, Edwin R.

doi:10.1111/j.1365-2222.2005.02231.x

Cited by 65 publications

(51 citation statements)

References 50 publications

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“…As expected, very few neutrophils were detected in the lungs of unchallenged mice. Similar to previously published data from other laboratories using the same model, [16][17][18][19] the number of neutrophils in the WT BALF reached nearly 10 6 cells/lung 8 hours after bacteria instillation and nearly 2 ϫ 10 6 cells/lung 24 hours after bacteria instillation. Myeloid-specific PTEN Ϫ/Ϫ mice showed a dramatic increase in bacteria-induced neutrophil recruitment.…”

Section: Accumulation Of Pten-null Neutrophils In Inflamed Lungs Is Esupporting

confidence: 80%

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

Jia

Pichavant

et al. 2009

Blood

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Neutropenia and related infections are the most important dose-limiting toxicities in anticancer chemotherapy and radiotherapy. In this study, we explored a new strategy for augmenting host defense in neutropenia-related pneumonia. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3-phosphatase that hydrolyzes PtdIns(3,4,5)P 3 . In myeloidspecific PTEN knockout mice, significantly more neutrophils were recruited to the inflamed lungs during neutropeniaassociated pneumonia. Using an adoptive transfer technique, we demonstrated that this enhancement could be caused directly by PTEN depletion in neutrophils. In addition, disruption of PTEN increased the recruitment of macrophages and elevated proinflammatory cytokines/chemokine levels in the inflamed lungs, which could also be responsible for the enhanced neutrophil recruitment. Depleting PTEN also significantly delayed apoptosis and enhanced the bacteria-killing capability of the recruited neutrophils. Finally, we provide direct evidence that enhancement of neutrophil function by elevating PtdIns(3,4,5)P 3 signaling can alleviate pneumonia-associated lung damage and decrease pneumonia-elicited mortality. Collectively, these results not only provide insight into the mechanism of action of PTEN and PtdIns(3,4,5)P 3 signaling pathway in modulating neutrophil function during lung infection and inflammation, but they also establish PTEN and related pathways as potential therapeutic targets for treating neutropenia-associated pneumonia. (Blood. 2009; 113:4930-4941)

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Section: Accumulation Of Pten-null Neutrophils In Inflamed Lungs Is Esupporting

confidence: 80%

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

Jia

Pichavant

et al. 2009

Blood

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“…It is noteworthy that the concentrations of elastase used in our in vitro studies are within the range of levels recorded in intact animals and humans. For example, elevated levels of neutrophil elastase (up to 400 ng/ml) were noted in BAL fluid from horses exposed to moldy hay (74). Further, levels of active neutrophil elastase ranging from 0.15 to 86 mM have been recorded in the epithelial lining fluid recovered by BAL from patients with cystic fibrosis (75,76).…”

Section: Discussionmentioning

confidence: 94%

Leukocyte Elastase Induces Lung Epithelial Apoptosis via a PAR-1–, NF-κB–, and p53-Dependent Pathway

Suzuki¹,

Yamashita²,

Zemans³

et al. 2009

Am J Respir Cell Mol Biol

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Leukocyte elastase induces apoptosis of lung epithelial cells via alterations in mitochondrial permeability, but the signaling pathways regulating this response remain uncertain. Here we investigated the involvement of proteinase-activated receptor-1 (PAR-1), the transcription factor NF-kB, and the protooncogene p53 in this pathway. Elastase-induced apoptosis of lung epithelial cells correlated temporally with activation of NF-kB, phosphorylation, and nuclear translocation of p53, increased p53 up-regulated modulator of apoptosis (PUMA) expression, and mitochondrial translocation of Bax resulting in enhanced permeability. Elastase-induced apoptosis was also prevented by pharmacologic inhibitors of NF-kB and p53 and by short interfering RNA knockdown of PAR-1, p53, or PUMA. These inhibitors prevented elastase-induced PUMA expression, mitochondrial translocation of Bax, increased mitochondrial permeability, and attenuated apoptosis. NF-kB inhibitors also reduced p53 phosphorylation. We conclude that elastase-induced apoptosis of lung epithelial cells is mediated by a PAR-1-triggered pathway involving activation of NF-kB and p53, and a PUMA-and Baxdependent increase in mitochondrial permeability leading to activation of distal caspases. Further, p53 contributes to elastaseinduced apoptosis by both transcriptional and post-transcriptional mechanisms.

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“…Augmented levels of the protease inhibitors α1-AT and α1-AT-RP may contribute to suppress elastase activity and indirectly inhibit elastase-related complement activation [72]. This protease increases after intense exercise in horse [43,73] as well as during airway inflammation [74], which often develops during prolonged movement and training [75][76][77]. Moreover, high levels of α1-AT have been found after intensified training in equine muscle biopsy [38].…”

Section: 2mentioning

confidence: 98%

Plasma protein changes in horse after prolonged physical exercise: A proteomic study

Scoppetta

Tartaglia

Renzone

et al. 2012

Journal of Proteomics

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Kinetics of pulmonary neutrophil recruitment and clearance in a natural and spontaneously resolving model of airway inflammation

Cited by 65 publications

References 50 publications

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

Leukocyte Elastase Induces Lung Epithelial Apoptosis via a PAR-1–, NF-κB–, and p53-Dependent Pathway

Plasma protein changes in horse after prolonged physical exercise: A proteomic study

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