Airway Mucosal Thickening and Bronchial Hyperresponsiveness Induced by Inhaled β2-Agonist in Mice

Tamaoki, Jun; Tagaya, Etsuko; Kawatani, Kiyomi; Nakata, Junko; Endo, Yui; Nagai, Atsushi

doi:10.1378/chest.126.1.205

Cited by 23 publications

(22 citation statements)

References 28 publications

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“…The dose of Bay 11-7082 used was chosen based on previous studies (40). The final DMSO concentrations used did not have any effect in our experiments (data not shown) and in other studies (37,41,42).…”

Section: Mouse Burn Injury Modelmentioning

confidence: 81%

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Sio

Ang

et al. 2010

The Journal of Immunology

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Acute lung injury (ALI) is a major cause of mortality in burn patients, even without direct inhalational injury. Identification of early mediators that instigate ALI after burn and of the molecular mechanisms by which they work are of high importance but remain poorly understood. We previously reported that an endogenous neuropeptide, substance P (SP), via binding neurokinin-1 receptor (NK1R), heightens remote ALI early after severe local burn. In this study, we examined the downstream signaling pathway following SP-NK1R coupling that leads to remote ALI after burn. A 30% total body surface area full-thickness burn was induced in male BALB/c wild-type (WT) mice, preprotachykinin-A (PPT-A) gene-deficient mice, which encode for SP, and PPT-A−/− mice challenged with exogenous SP. Local burn injury induced excessive SP-NK1R signaling, which activated ERK1/2 and NF-κB, leading to significant upregulation of cyclooxygenase (COX)-2, PGE metabolite, and remote ALI. Notably, lung COX-2 levels were abrogated in burn-injured WT mice by L703606, PD98059, and Bay 11-7082, which are specific NK1R, MEK-1, and NF-κB antagonists, respectively. Additionally, burn-injured PPT-A−/− mice showed suppressed lung COX-2 levels, whereas PPT-A−/− mice injected with SP showed augmented COX-2 levels postburn, and administration of PD98059 and Bay 11-7082 to burn-injured PPT-A−/− mice injected with SP abolished the COX-2 levels. Furthermore, treatment with parecoxib, a selective COX-2 inhibitor, attenuated proinflammatory cytokines, chemokines, and ALI in burn-injured WT mice and PPT-A−/− mice injected with SP. To our knowledge, we show for the first time that SP-NK1R signaling markedly elevates COX-2 activity via ERK1/2 and NF-κB, leading to remote ALI after burn.

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Section: Mouse Burn Injury Modelmentioning

confidence: 81%

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Sio

Ang

et al. 2010

The Journal of Immunology

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“…t-Test: *P Ͻ 0.01 vs. vehicle; n ϭ 4 experiments for A and B and n ϭ 5 for C and D. AC assay. AC activity was measured by a modification of the method of Salomon et al (10), as we previously described (12). When the AC assays were performed using crude membranes from AC6Tg mice heart, manganese instead of magnesium was used in the assay buffer to obtain maximum enzymatic catalytic activity because AC6 is stimulated more by manganese than by magnesium (16).…”

Section: Methodsmentioning

confidence: 99%

Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase

Iwatsubo

Bravo²,

Uechi

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Vatner SF, Ishikawa Y. Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol 302: H2622-H2628, 2012. First published April 13, 2012; doi:10.1152/ajpheart.00190.2012.-Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to translate from genes to drugs. This investigation examines an antiviral drug, which also has an action to selectively inhibit type 5 adenylyl cyclase (AC5), a pharmaceutical correlate of the AC5 knockout (KO) model, which exhibits longevity and stress resistance. Our objective was to examine the extent to which pretreatment with this drug, adenine 9-␤-D-arabinofuranoside (Ara-A), favorably ameliorates the development of heart failure (HF). Ara-A exhibited selective inhibition for AC5 compared with the other major cardiac AC isoform, AC6, i.e., it reduced AC activity significantly in AC5 transgenic (Tg) mice, but not in AC5KO mice and had little effect in either wild-type or AC6Tg mice. Permanent coronary artery occlusion for 3 wk in C57Bl/6 mice increased mortality and induced HF in survivors, as reflected by reduced cardiac function, while increasing cardiac fibrosis. The AC5 inhibitor Ara-A significantly improved all of these end points and also ameliorated chronic isoproterenol-induced cardiomyopathy. As with the AC5KO mice, Ara-A increased mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation. A MEK inhibitor abolished the beneficial effects of the AC5 inhibitor in the HF model, indicating the involvement of the downstream MEK-ERK pathway of AC5. Our data suggest that pharmacological AC5 inhibition may serve as a new therapeutic approach for HF. heart failure; type 5 adenylyl cyclase inhibition; adenine 9-␤-Darabinofuranoside DESPITE GAINS IN THE TREATMENT of heart failure (HF) with both angiotensin and ␤-adrenergic receptor (␤-AR) blockers, HF still remains a major cause of death and disability. In addition, some patients do not tolerate ␤-AR blocking therapy (2). It is conceivable that inhibiting mechanisms distal to the ␤-AR signaling pathway, identified from genetically engineered mouse models, might be a novel approach. While there have been numerous potential therapeutic approaches discovered from studies in genetically engineered mice in the past two decades, there are relatively few of these discoveries that have been translated to the bedside, mainly because it is difficult to translate the effects of disrupting a gene in a mouse to therapy in patients with HF.The goal of this investigation was to examine the extent to which a pharmacological inhibitor of type 5 adenylyl cyclase (AC5), 9-␤-D-arabinofuranoside (Ara-A), could mimic the salutary effects observed in the AC5 knockout (KO) mice model, which protects against cardiac stress (10, 11) and increases longevity (15). The first goal was to determine the extent to which Ara-A selectively inhibits AC5...

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“…5 ml/kg, i.p.) was given to mice 1 h before CLP (19,20). It was found that pretreatment with PD98059 at a dose of 10 mg/kg effectively suppressed the activation of ERK-NF-B pathway in sepsis, as evidenced by a significant reduction in the phosphorylation of ERK1/2, degradation of IB␣, and DNA-binding activity of nuclear NF-B in lung and liver (Figs.…”

Section: Inhibition Of Erk-nf-b Pathway Attenuates Nahs-induced Inflamentioning

confidence: 96%

“…; Calbiochem), or vehicle (DMSO/0.9%NaCl (1:50), 5 ml/kg, i.p.) was given to mice 1 h before CLP (19,20). NaHS (10 mg/kg, i.p.…”

Section: Induction Of Sepsismentioning

confidence: 99%

Endogenous Hydrogen Sulfide Regulates Inflammatory Response by Activating the ERK Pathway in Polymicrobial Sepsis

Zhang

Moochhala

Bhatia

2008

The Journal of Immunology

110

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Hydrogen sulfide (H2S) up-regulates inflammatory response in several inflammatory diseases. However, to date, little is known about the molecular mechanism by which H2S provokes the inflammatory response in sepsis. Thus, the aim of this study was to investigate the signaling pathway underlying the proinflammatory role of H2S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP and treated with dl-propargylglycine (PAG; 50 mg/kg i.p., an inhibitor of H2S formation), NaHS (10 mg/kg, i.p., an H2S donor), or saline. PAG was administered 1 h before CLP, whereas NaHS was given at the time of CLP. CLP-induced sepsis resulted in a time-dependent increase in the synthesis of endogenous H2S. Maximum phosphorylation of ERK1/2 and degradation of IκBα in lung and liver were observed 4 h after CLP. Inhibition of H2S formation by PAG significantly reduced the phosphorylation of ERK1/2 in lung and liver 4 h after CLP, coupled with decreased degradation of IκBα and activation of NF-κB. In contrast, injection of NaHS significantly enhanced the activation of ERK1/2 in lung and liver, therefore leading to a further rise in tissue NF-κB activity. As a result, pretreatment with PAG significantly reduced the production of cytokines and chemokines in sepsis, whereas exogenous H2S greatly increased it. In addition, pretreatment with PD98059, an inhibitor of ERK kinase (MEK-1), significantly prevented NaHS from aggravating systemic inflammation in sepsis. In conclusion, the present study shows for the first time that H2S may regulate systemic inflammatory response in sepsis via ERK pathway.

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Airway Mucosal Thickening and Bronchial Hyperresponsiveness Induced by Inhaled β2-Agonist in Mice

Cited by 23 publications

References 28 publications

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Substance P Upregulates Cyclooxygenase-2 and Prostaglandin E Metabolite by Activating ERK1/2 and NF-κB in a Mouse Model of Burn-Induced Remote Acute Lung Injury

Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase

Endogenous Hydrogen Sulfide Regulates Inflammatory Response by Activating the ERK Pathway in Polymicrobial Sepsis

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