Didecyldimethylammonium chloride induces pulmonary fibrosis in association with TGF-β signaling in mice

Ohnuma-Koyama, Aya; Yoshida, Toshinori; Tajima-Horiuchi, Haruka; Takahashi, Naofumi; Yamaguchi, Satoru; Ohtsuka, Ryoichi; Takeuchi-Kashimoto, Yukiko; Kuwahara, Maki; Takeda, Makio; Nakashima, Nobuaki; Harada, Takanori

doi:10.1016/j.etp.2013.02.003

Cited by 15 publications

(9 citation statements)

References 38 publications

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“…Previous work has shown that even small increases in TGF‐β expression can have profound effects in the local environment and changes in receptors or second messengers such as SMAD3 can amplify the TGF‐β associated responsiveness . Given that TGF‐β is a common mediator of fibrosis in tissue and organ systems and that significant increases are found in both TGF‐β 1 and TGF‐β receptors in SSCT of CTS patients, we chose to focus on this pathway as a potential regulator and therapeutic target …”

Section: Discussionmentioning

confidence: 99%

“…Patient SSCT fibroblasts were treated with TGF‐β 1 and a significant increase in SMAD activity was evident. In addition, we looked to specifically block TGF‐β signaling using the TβRI inhibitor, SD208 . Upon treatment, SMAD activation was reduced to control levels indicating that TβRI blocks canonical SMAD3 signaling in patient SSCT fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

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TGF‐β signaling regulates fibrotic expression and activity in carpal tunnel syndrome

Gingery

Yang

Passe

et al. 2014

Journal Orthopaedic Research

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Fibrosis of the subsynovial connective tissue (SSCT) is a predominant feature of carpal tunnel syndrome (CTS). While the nature of CTS has been extensively studied, little is known about the etiology of this disease. We investigated SSCT tissue from patients with CTS and control subjects using fibrosis arrays and cell culture analysis. Two-fold changes in fibrotic gene expression were found in multiple genes from patient SSCT using fibrosis arrays. This data was confirmed via qRT-PCR on a subset of genes; collagen I (Col1), collagen III (Col3), connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and SMAD3 (p<0.05), which significantly corroborate the fold changes found in the fibrosis arrays. To further explore the nature of SSCT fibrosis, cells were isolated from patient and control tissue. Col1, Col3, TGF-β, and SMAD3 were highly expressed in patient SSCT fibroblasts as compared to control (p<0.05). Further, fibrotic genes expression was decreased by inhibiting TGF-β receptor I (TβRI) activity (p<0.05). TGF-β second messenger SMAD activity was significantly activated in SSCT fibroblasts from patients and this activation was abrogated by inhibiting TβRI signaling (p<0.05). These findings suggest that blocking TGF-β signaling may be an important therapeutic approach to treating the underlying fibrosis of SSCT in CTS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TGF‐β signaling regulates fibrotic expression and activity in carpal tunnel syndrome

Gingery

Yang

Passe

et al. 2014

Journal Orthopaedic Research

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“…Furthermore, ammonia inhalation to rats causes increased oxidative stress, decreased antioxidant enzymes and acute lung injury which was attenuated following α-ketoglutarate treatment (Ali et al, 2012). Ammonia induced acute lung injury have also been shown in rabbits associated with an elevated airway pressure and a decrease in PaO2 (Sjöblom et al, 1999) and has been shown to induce lung fibrosis (Ohnuma-Koyama et al, 2013). Ammonia and enzymatically active urease released from parasitic cells of Coccidioides posadasii contribute to host tissue damage and exacerbate the severity of coccidioidal lung infections (Mirbod et al, 2002;Mirbod-Donovan et al, 2005;Wise et al, 2013).…”

Section: Lungmentioning

confidence: 99%

Ammonia toxicity: from head to toe?

et al. 2016

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Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.

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“…The pulmonary toxicity of DDAC has been demonstrated in several studies. Intratracheal instillation of DDAC caused alveolar cell injuries, inflammation and fibrosis in the rodent lung (Ohnuma et al, 2010;Ohnuma-Koyama et al, 2013;Shim et al, 2013). Interstitial pneumonia and inflammatory cell infiltration to the lung were observed in rats that inhaled DDAC for 2 weeks (Lim and Chung, 2014).…”

Section: Introductionmentioning

confidence: 99%

Acute pulmonary toxicity and inflammation induced by combined exposure to didecyldimethylammonium chloride and ethylene glycol in rats

Kwon

Kim

et al. 2016

J. Toxicol. Sci.

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Didecyldimethylammonium chloride (DDAC), an antimicrobial agent, has been reported to induce pulmonary toxicity in animal studies. DDAC is frequently used in spray-form household products in combination with ethylene glycol (EG). The purpose of this study was to evaluate the toxic interaction between DDAC and EG in the lung. DDAC at a sub-toxic dose (100 μg/kg body weight) was mixed with a non-toxic dose of EG (100 or 200 μg/kg body weight), and was administrated to rats via intratracheal instillation. Lactate dehydrogenase activity and total protein content in the bronchoalveolar lavage fluid (BALF) were not changed by singly treated DDAC or EG, but significantly enhanced at 1 d after treatment with the mixture, with the effect dependent on the dose of EG. Total cell count in BALF was largely increased and polymorphonuclear leukocytes were predominantly recruited to the lung in rats administrated with the mixture. Inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6 also appeared to be increased by the mixture of DDAC and EG (200 μg/kg body weight) at 1 d post-exposure, which might be associated with the increase in inflammatory cells in lung. BALF protein content and inflammatory cell recruitment in the lung still remained elevated at 7 d after the administration of DDAC with the higher dose of EG. These results suggest that the combination of DDAC and EG can synergistically induce pulmonary cytotoxicity and inflammation, and EG appears to amplify the harmful effects of DDAC on the lung. Therefore pulmonary exposure to these two chemicals commonly found in commercial products can be a potential hazard to human health.

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Didecyldimethylammonium chloride induces pulmonary fibrosis in association with TGF-β signaling in mice

Cited by 15 publications

References 38 publications

TGF‐β signaling regulates fibrotic expression and activity in carpal tunnel syndrome

TGF‐β signaling regulates fibrotic expression and activity in carpal tunnel syndrome

Ammonia toxicity: from head to toe?

Acute pulmonary toxicity and inflammation induced by combined exposure to didecyldimethylammonium chloride and ethylene glycol in rats

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