Resolution of Experimental Lung Injury by Monocyte-Derived Inducible Nitric Oxide Synthase

D’Alessio, Franco R.; Tsushima, Kenji; Aggarwal, Neil R.; Mock, Jason R.; Eto, Yoshiki; Garibaldi, Brian T.; Files, D. Clark; Avalos, Claudia R.; Rodriguez, Jackie V.; Waickman, Adam T.; Reddy, Sekhar P.; Pearse, David B.; Sidhaye, Venkataramana K.; Hassoun, Paul M.; Crow, Michael T.; King, Landon S.

doi:10.4049/jimmunol.1102606

Cited by 42 publications

(46 citation statements)

References 62 publications

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“…We anesthetized and injected mice as previously described (7,17). We used Escherichia coli LPS (O55:B5, catalogue number L2880; Sigma Chemical Company, St. Louis, MO) at 0.3 mg/g mouse or sterile water (vehicle control).…”

Section: Animal Injection and Processingmentioning

confidence: 99%

“…We used Escherichia coli LPS (O55:B5, catalogue number L2880; Sigma Chemical Company, St. Louis, MO) at 0.3 mg/g mouse or sterile water (vehicle control). We processed mice on Days 1 to 3 after LPS exposure, as described elsewhere (7,17) and in the online supplement.…”

Section: Animal Injection and Processingmentioning

confidence: 99%

“…We harvested bone marrow (BM) cells from ADORA2A 2/2 and CD45.1 mice, and recipient mice (5-6 wk) were irradiated and housed as described elsewhere (17) and in the online supplement. Two hours after irradiation, we injected 1.5 3 10 6 BM cells intravenously (17).…”

Section: Bone Marrow Isolation Adoptive Transfer and Chimerasmentioning

confidence: 99%

“…Classically activated M1-type alveolar macrophages are an important component of the initial innate immune response, and they secrete the proinflammatory cytokines TNF-a and macrophage inflammatory protein 2 (MIP-2) to augment that response. They also express CD86 and CD40, costimulatory molecules capable of regulating inflammation in innate immunity via communication with lymphocytes or neutrophils (17,18). Janssen and colleagues demonstrated that resident alveolar macrophages demonstrate plasticity through a cycle of inflammation and resolution (10) in a lung injury model, first manifesting a proinflammatory phenotype critical to the propagation of lung inflammation, but subsequently developing an anti-inflammatory profile crucial for resolution (10,13,14,19,20).…”

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confidence: 99%

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Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Aggarwal¹,

D’Alessio²,

Eto³

et al. 2013

Am J Respir Cell Mol Biol

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Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting antiinflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A2/2 mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A 2/2 mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A2/2 mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A 2/2 mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A 2/2 bone marrow cells into irradiated ADORA2A2/2 mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway.

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Section: Animal Injection and Processingmentioning

confidence: 99%

Section: Animal Injection and Processingmentioning

confidence: 99%

Section: Bone Marrow Isolation Adoptive Transfer and Chimerasmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Aggarwal¹,

D’Alessio²,

Eto³

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

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show abstract

“…The effect of obesity on exhaled NO levels in mildly obese humans without diagnosed asthma is still unclear [25,26]. This effect may be significant since NO is involved in the pulmonary immune defense and repair [27,28] and NO is increased in the bronchoalveolar lavage (BAL) fluid and lungs of patients during ARDS development [29].…”

Section: Introductionmentioning

confidence: 99%

Exhaled Breath Condensate Nitrate Levels are Inversely Associated with the Body Mass Index of Patients without Respiratory Disease

Fern

ezBustamante²,

Seres³

et al. 2015

J Pulm Respir Med

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Ulinastatin promotes macrophage efferocytosis and ameliorates lung inflammation via the ERK5/Mer signaling pathway

Shao

Xie

et al. 2022

FEBS Open Bio

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Acute lung injury (ALI) is a pneumonic response characterized by neutrophil infiltration. Macrophage efferocytosis is the process whereby macrophages remove apoptotic cells, and is required for ALI inflammation to subside. The glycoprotein ulinastatin (UTI) has an anti-inflammatory effect during the acute stages of ALI, but its effect on efferocytosis and the subinflammatory stage of ALI is unclear. Extracellular signal-regulated kinase 5 (ERK5) is a key protein in efferocytosis, and we thus hypothesized that it may be activated by UTI to regulate efferocytosis and the resolution of pneumonia. To test this hypothesis, here we monitored phagocytosis of macrophages through in vivo and in vitro experiments. Pulmonary edema, neutrophil infiltration, protein exudation, and inflammatory factor regression were observed on days 1, 3, 5, and 7 in vivo. RAW264.7 cells were pretreated with different concentrations of UTI and ERK5 inhibitors, and the expression of tyrosine-protein kinase Mer (Mer) protein on macrophage membrane was detected. UTI increased the phagocytosis of apoptotic neutrophils by macrophages in vitro and in vivo, and promoted the resolution of pneumonia. The protein expression of ERK5 and Mer increased with UTI concentration, while the expression of Mer was down-regulated by ERK5 inhibitors. Therefore, our results suggest that UTI enhances efferocytosis and reduces lung inflammation and injury through the ERK5/Mer signaling pathway, which may be one of the targets of UTI in the treatment of lung injury.Acute lung injury (ALI) is a critical clinical illness of common occurrence and is a pneumonic reaction characterized by neutrophil infiltration [1]. The pathophysiological process of ALI can be roughly divided into the acute inflammatory stage and the subsiding inflammatory stage. In the subsiding phase of inflammation, macrophages directly engulf and clear apoptotic neutrophils to repair damaged tissues, a process called efferocytosis, which promotes the recovery of lung epithelial and endothelial functions and the reconstruction of lung tissue structure. If apoptotic cells are not cleared in time, many intracellular danger signaling molecules are released by secondary cell necrosis, which further hinders tissue repair. Therefore, promoting the regression of pneumonia will shorten the pathophysiological process of ALI and reduce lung injury [2,3].Ulinastatin (UTI), a commonly used drug in clinical practice, is an endogenous molecule with actions against infectious pathogens and its pharmacological Abbreviations ALI, acute lung injury; ERK5, extracellular signalregulated kinase 5; Mer, tyrosine-protein kinase Mer; UTI, ulinastatin.

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Resolution of Experimental Lung Injury by Monocyte-Derived Inducible Nitric Oxide Synthase

Cited by 42 publications

References 62 publications

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Exhaled Breath Condensate Nitrate Levels are Inversely Associated with the Body Mass Index of Patients without Respiratory Disease

Ulinastatin promotes macrophage efferocytosis and ameliorates lung inflammation via the ERK5/Mer signaling pathway

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