DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia

Yan, Yonghong; Lin, Ping; Zhang, Weidong; Tan, Shirui; Zhou, Xikun; Li, Rongpeng; Pu, Qinqin; Koff, Jonathan L.; Dhasarathy, Archana; Ma, Feng; Deng, Xin; Jiang, Jianxin; Wu, Min

doi:10.4049/jimmunol.1601001

Cited by 33 publications

(34 citation statements)

References 64 publications

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“…ROS generated by hyperoxia and the resulting excessive oxidative stress are important working mechanisms for lung injury [ 29,30] . Lee et al[ 31,32] found that AEC Ⅱ was the primary target cells for ROS.…”

Section: Discussionmentioning

confidence: 99%

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

Wang

Sha

et al. 2020

Preprint

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Background: Long-term mechanical ventilation with hyperoxia can induce lung injury. General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a relatively short period of time. It remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact on or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia may cause lung injury in rats and whether deferoxamine (DFO), a ferrous ion chelator, could mitigate such injury to the lungs and explore the possible mechanism. Methods: Twenty-four SD rats were randomly divided into 3 groups (n=8/group): mechanical ventilated with normoxia group (MV group, FiO2=21%), with hyperoxia group (HMV group, FiO2=90%), or with hyperoxia + DFO group (HMV+DFO group, FiO2=90%). Mechanical ventilation under different oxygen concentrations was given for 4 hours.The HMV+DFO group received continuous intravenous infusion of DFO at 200mg•kg-1•d-1, while the MV and HMV groups received an equal volume of normal saline. Carotid artery cannulation was carried out to monitor the blood gas parameters under mechanical ventilation for 2 hours and 4 hours, respectively, and the PaO2/FiO2 ratio was calculated. After 4 hours ventilation, the right anterior lobe of the lung and BALF from the right lung was sampled for pathological and biochemical assays. Results: PaO2 in the HMV and HMV+DFO groups were significantly higher, but the PaO2/FiO2 ratio were significantly lower than those of the MV group (all p<0.01). The lung pathological scores and the wet-to-dry weight ratio (W/D) in the HMV and HMV+DFO groups were significantly higher than those of the MV group, but score and the W/D ratio were reduced by DFO (p<0.05). Biochemically, HMV resulted in significant reductions in SP-C, SP-D, and GR levels and elevation of XOD in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO. Conclusions: Mechanical ventilation with hyperoxia for 4 hours induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.

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Section: Discussionmentioning

confidence: 99%

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

Wang

Sha

et al. 2020

Preprint

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“…Culture cells treated as above were washed with PBS twice, and prepared in ice‐cold RIPA (Thermofisher, Waltham, MA) supplemented with protease and phosphatase inhibitor cocktail (Thermofisher). Immunoblot analysis was performed and membranes were blotted with antibodies to NLRP3, AIM2, NLRC4, microtubule‐associated protein 1 light chain 3A/B (LC3A/B), caspase‐1 and β ‐actin (Cell Signaling Technology, Danvers, MA) …”

Section: Methodsmentioning

confidence: 99%

Bacterial Type I CRISPR‐Cas systems influence inflammasome activation in mammalian host by promoting autophagy

Wang

Zhou

et al. 2019

Immunology

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The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated systems (CRISPR-Cas) systems in prokaryotes function at defending against foreign DNAs, providing adaptive immunity to maintain homeostasis. CRISPR-Cas may also influence immune regulation ability in mammalian cells through alterations of pathogenic extent and nature. Recent research has implied that Type I CRISPR-Cas systems of Pseudomonas aeruginosa strain UCBPP-PA14 impede recognition by Toll-like receptor 4, and decrease pro-inflammatory responses both in vitro and in vivo. However, the molecular mechanism by which CRISPR-Cas systems affect host immunity is largely undemonstrated. Here, we explored whether CRISPR-Cas systems can influence autophagy to alter the activation of inflammasome. Using the wild-type PA14 and total CRISPR-Cas region deletion (ΔTCR) mutant strain, we elucidated the role and underlying mechanism of Type I CRISPR-Cas systems in bacterial infection, and showed that CRISPR-Cas systems impacted the release of mitochondrial DNA and induction of autophagy. CRISPR-Cas deficiency led to an increase of mitochondrial DNA release, a decrease in autophagy, an increase of inflammasome activation and, ultimately, an elevation of pro-inflammatory response. Our findings illustrate a new important mechanism by which Type I CRISPR-Cas systems control their virulence potency to evade host defense.

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“…Triplicates were done for each sample and control. Background was corrected by using blanks containing dye alone (32).…”

Section: Nitroblue Tetrazolium Assaymentioning

confidence: 99%

SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt–STAT5–Trib1 Circuit in Pseudomonas aeruginosa Infection

Qin

Zhou

et al. 2020

Front. Immunol.

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SHIP-1 is an inositol phosphatase that hydrolyzes phosphatidylinositol 3-kinase (PI3K) products and negatively regulates protein kinase B (Akt) activity, thereby modulating a variety of cellular processes in mammals. However, the role of SHIP-1 in bacterial-induced sepsis is largely unknown. Here, we show that SHIP-1 regulates inflammatory responses during Gram-negative bacterium Pseudomonas aeruginosa infection. We found that infected-SHIP-1 −/− mice exhibited decreased survival rates, increased inflammatory responses, and susceptibility owing to elevated expression of PI3K than wild-type (WT) mice. Inhibiting SHIP-1 via siRNA silencing resulted in lipid raft aggregates, aggravated oxidative damage, and bacterial burden in macrophages after PAO1 infection. Mechanistically, SHIP-1 deficiency augmented phosphorylation of PI3K and nuclear transcription of signal transducer and activator of transcription 5 (STAT5) to induce the expression of Trib1, which is critical for differentiation of M2 but not M1 macrophages. These findings reveal a previously unrecognized role of SHIP-1 in inflammatory responses and macrophage homeostasis during P. aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis.

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DNA Repair Interacts with Autophagy To Regulate Inflammatory Responses to Pulmonary Hyperoxia

Cited by 33 publications

References 64 publications

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

Bacterial Type I CRISPR‐Cas systems influence inflammasome activation in mammalian host by promoting autophagy

SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt–STAT5–Trib1 Circuit in Pseudomonas aeruginosa Infection

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