Activation of alveolar macrophages in acid-injured lung in rats: Different effects of pentoxifylline on tumor necrosis factor-α and nitric oxide production

Kudoh, Ichidai; Miyazaki, Hiroshi; Ohara, Maria; Fukushima, Jun; Tazawa, Toshiharu; Yamada, Hiroshi

doi:10.1097/00003246-200108000-00020

Cited by 27 publications

(31 citation statements)

References 30 publications

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“…In this study, we used the model of acid-induced lung injury, a model of aseptic ARDS (2). Similarly to septic lung injury, we found that alveolar macrophages in acid-induced lung injury acquire a classical (M1) activation phenotype in the early phase that is characterized by increased iNOS expression and accumulation of NO metabolites, which are known to contribute to the pathogenesis of ARDS (4,13,(15)(16)(17)(18). Furthermore, we identified the onset of the resolving phase of inflammation, during which suppression of iNOS and predominance of Arg-1, Fizz1, and Ym1 expression, features of M2 polarization, take place.…”

Section: Discussionmentioning

confidence: 94%

“…It is well established that macrophages play a central role in the pathogenesis of ARDS (4,5,12,13). Most of the studies using animal models examined the role of macrophages in LPS-induced lung injury, a model that resembles septic ARDS (11,18,20).…”

Section: Discussionmentioning

confidence: 99%

“…Because it is well established that suppression of iNOS and subsequent inhibition of M1 activation (4,13,(15)(16)(17)(18), as well as induction of M2 (20), can confer protection in ARDS, the identification of molecules that promote this mechanism in vivo is of the utmost importance. However, Akt2 suppression and M2 macrophages impair the innate immune response against live bacteria, such as P. aeruginosa, which limits the use of M2 induction for the protection from gastric acid aspiration-induced lung injury.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages play an important role in the pathogenesis of lung injury, initiating the inflammatory response and promoting neutrophil infiltration and tissue damage in the lung (4,5,(8)(9)(10)(11)(12)(13). However, based on environmental stimuli, macrophages can possess the classical (M1) or alternative activation (M2) phenotype (14).…”

mentioning

confidence: 99%

“…Classically activated or M1 macrophages express high levels of inducible NO synthase (iNOS), generate NO, secrete IL-12b, and are prominent in the acute phase of inflammation (14). Genetic depletion or pharmacologic inhibition of iNOS was shown to confer protection against lung injury in several animal models (4,13,(15)(16)(17)(18), suggesting a crucial role for M1 macrophages in the pathogenesis of acute lung injury (ALI). Alternative macrophage activation, or M2, is characterized by high levels of arginase-1 (Arg-1), found-in-inflammatory zone-1 (Fizz1), chitinase-3-like-3 (Ym1), and macrophage galactose C-type lectin 1 and 2 (MGL1, MGL2) (8,9,19).…”

mentioning

confidence: 99%

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Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

146

106

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Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2−/− mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2−/− mice compared with WT mice. Alveolar macrophages from acid-injured Akt2−/− mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2−/− mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2−/− mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2−/− macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Vergadi

Vaporidi

Theodorakis

et al. 2014

The Journal of Immunology

146

106

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Aspiration Pneumonia and Pneumonitis

Marik

2010

Handbook of Evidence-Based Critical Care

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Glossogyne tenuifolia acts to inhibit inflammatory mediator production in a macrophage cell line by downregulating LPS-induced NF-κB

Wang

Ding

et al. 2004

J Biomed Sci

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Glossogyne tenuifolia (hsiang-ju) (GT) is a traditional antipyretic herb used in Chinese medicine; however, no information is available to explain its action. The objective of this research was to elucidate the molecular pharmacological activity and the effective components in the ethanol extract of GT. We found that GT had potent anti-inflammatory effects on the lipopolysaccharide (LPS)-activated murine macrophages, RAW264.7. GT downregulated LPS-induced expression of inducible nitric oxide synthase (iNOS) by blocking its transcription. GT also caused a dose-dependent inhibition of the release of prostaglandin E(2) by repressing the promoter activity of the inducible cyclooxygenase (COX-2) gene. Moreover, GT exerted a dose-dependent inhibition of the LPS-stimulated release of the proinflammatory cytokines, TNF-alpha, IL-1 beta, IL-6, and IL-12. To determine the mechanism by which GT inhibits LPS signaling, we focused on nuclear factor-kappa B (NF-kappa B) activation. Western blot analysis revealed that GT abolished LPS-induced inhibitor-kappa B phosphorylation. The electrophoretic mobility shift assay demonstrated that GT abolished LPS-mediated kappa B DNA binding activity. Moreover, macrophages were transfected with a vector coding for the luciferase reporter gene under the control of NF-kappa B cis-acting elements, and the transfected macrophages showed that the LPS-stimulated luciferase activity was GT-sensitive. These results suggest that GT attenuates inflammatory mediator synthesis of activated macrophages through an NF-kappa B-dependent pathway. The active components of GT were identified as oleanolic acid and luteolin-7-glucoside. Both of these compounds inhibited LPS-stimulated inflammatory mediator production and NF-kappa B activation. We conclude that GT inhibits NF-kappa B-mediated gene expression and downregulates inflammatory mediator production in murine macrophages.

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Activation of alveolar macrophages in acid-injured lung in rats: Different effects of pentoxifylline on tumor necrosis factor-α and nitric oxide production

Cited by 27 publications

References 30 publications

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

Aspiration Pneumonia and Pneumonitis

Glossogyne tenuifolia acts to inhibit inflammatory mediator production in a macrophage cell line by downregulating LPS-induced NF-κB

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