Protective Role of Simvastatin on Lung Damage Caused by Burn and Cotton Smoke Inhalation in Rats

Bellı, Sedat; Başaran, Ö.; Özdemir, Binnaz Handan; Türkoğlu, Suna; Karabay, Gülten; Kut, Altuğ; Karakayalı, H.; Haberal, Mehmet

doi:10.1016/j.jss.2010.01.035

Cited by 13 publications

(14 citation statements)

References 38 publications

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“…The potential role for statins in the treatment of ALI is an area of ongoing investigation, and is supported by abundant in vitro data (2, 3, 13), findings in animal models (1,(14)(15)(16)(17), numerous observational reports involving relevant patient populations (18)(19)(20)(21), as well as data from recent human studies (22,23). These drugs are recognized to have pleiotropic properties, including numerous direct effects on EC signaling and activation.…”

Section: Discussionmentioning

confidence: 97%

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

Chen

Sharma

Rizzo

et al. 2014

Am J Respir Cell Mol Biol

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The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 mM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and b-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPSinduced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.

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Section: Discussionmentioning

confidence: 97%

Role of Claudin-5 in the Attenuation of Murine Acute Lung Injury by Simvastatin

Chen

Sharma

Rizzo

et al. 2014

Am J Respir Cell Mol Biol

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“…Levels of iNOS were significantly lower in treatment groups when compared to controls but not when compared to sham animals, and lipid peroxidation levels (measured by lung MDA) were significantly lower in treatment groups when compared to both control and sham [72]. In addition, they found significantly higher levels of glutathione concentrations in treatment groups when compared to both sham and control injury, implying protection against lipid peroxidation, oxidative stress, and apoptosis in injured mice treated with statins [72]. The application of this therapeutic may be limited by systemic effects of the drug.…”

Section: Hmg-coa Reductase Inhibitionmentioning

confidence: 82%

“…They found significant improvement in histopathological scores, leukocyte infiltration and pneumocyte apoptosis in treatment groups when compared to controls, but did not note a significant difference in MPO levels between groups [72]. Levels of iNOS were significantly lower in treatment groups when compared to controls but not when compared to sham animals, and lipid peroxidation levels (measured by lung MDA) were significantly lower in treatment groups when compared to both control and sham [72]. In addition, they found significantly higher levels of glutathione concentrations in treatment groups when compared to both sham and control injury, implying protection against lipid peroxidation, oxidative stress, and apoptosis in injured mice treated with statins [72].…”

Section: Hmg-coa Reductase Inhibitionmentioning

confidence: 88%

“…Administration of these medications have also been reported to result in immunomodulatory and anti-inflammatory effects including decreased proinflammatory transcription factors and enzymes, adhesion molecules, and chemoattractant proteins [70,71]. Based on this knowledge, Belli et al administered oral statins to rats after burn and smoke inhalation injury to identify any possible protective effect on pulmonary injury [72]. They found significant improvement in histopathological scores, leukocyte infiltration and pneumocyte apoptosis in treatment groups when compared to controls, but did not note a significant difference in MPO levels between groups [72].…”

Section: Hmg-coa Reductase Inhibitionmentioning

confidence: 99%

“…Based on this knowledge, Belli et al administered oral statins to rats after burn and smoke inhalation injury to identify any possible protective effect on pulmonary injury [72]. They found significant improvement in histopathological scores, leukocyte infiltration and pneumocyte apoptosis in treatment groups when compared to controls, but did not note a significant difference in MPO levels between groups [72]. Levels of iNOS were significantly lower in treatment groups when compared to controls but not when compared to sham animals, and lipid peroxidation levels (measured by lung MDA) were significantly lower in treatment groups when compared to both control and sham [72].…”

Section: Hmg-coa Reductase Inhibitionmentioning

confidence: 99%

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Emerging therapies for smoke inhalation injury: a review

et al. 2020

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Background: Smoke inhalation injury increases overall burn mortality by up to 20 times. Current therapy remains supportive with a failure to identify an optimal or targeted treatment protocol for smoke inhalation injury. The goal of this review is to describe emerging therapies that are being developed to treat the pulmonary pathology induced by smoke inhalation injury with or without concurrent burn injury. Main body: A comprehensive literature search was performed using PubMed (1995-present) for therapies not approved by the U.S. Food and Drug Administration (FDA) for smoke inhalation injury with or without concurrent burn injury. Therapies were divided based on therapeutic strategy. Models included inhalation alone with or without concurrent burn injury. Specific animal model, mechanism of action of medication, route of administration, therapeutic benefit, safety, mortality benefit, and efficacy were reviewed. Multiple potential therapies for smoke inhalation injury with or without burn injury are currently under investigation. These include stem cell therapy, anticoagulation therapy, selectin inhibition, inflammatory pathway modulation, superoxide and peroxynitrite decomposition, selective nitric oxide synthase inhibition, hydrogen sulfide, HMG-CoA reductase inhibition, proton pump inhibition, and targeted nanotherapies. While each of these approaches shows a potential therapeutic benefit to treating inhalation injury in animal models, further research including mortality benefit is needed to ensure safety and efficacy in humans. Conclusions: Multiple novel therapies currently under active investigation to treat smoke inhalation injury show promising results. Much research remains to be conducted before these emerging therapies can be translated to the clinical arena.

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