Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis

Liu, Xingjian; Khadtare, Nikhil; Patel, Hardek; Stephani, Ralph A.; Cantor, Jerome O.

doi:10.1007/s00408-018-0103-0

Cited by 6 publications

(3 citation statements)

References 37 publications

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“…The parameters of inflammation examined at 2 to 4 weeks post-AM were the same as those used to evaluate BLM-induced pulmonary fibrosis, and the results were similar to those seen with that model. Pretreatment with HJP272 produced significant reductions in all of these variables compared to AM alone, while post-treatment was ineffective, providing additional support for the hypothesis that the course of injury and repair is programmed at a very early stage of the inflammatory process [26]. The temporal effects of HJP272 were again most evident by examining lung morphological changes, which showed a much more limited fibrotic reaction in the pretreatment group (Figure 6).…”

Section: Am-induced Pulmonary Fibrosismentioning

confidence: 67%

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Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Cantor

2024

IJMS

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Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a “gatekeeper” for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.

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Section: Am-induced Pulmonary Fibrosismentioning

confidence: 67%

“…As with the BLM model, HJP272 was administered intraperitoneally 1 h before treatment with AM or 24 h afterward [26]. The parameters of inflammation examined at 2 to 4 weeks post-AM were the same as those used to evaluate BLM-induced pulmonary fibrosis, and the results were similar to those seen with that model.…”

Section: Am-induced Pulmonary Fibrosismentioning

confidence: 80%

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Cantor

2024

IJMS

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“…Amiodarone (AD) is an effective antiarrhythmic drug that has been linked to lung damage and can lead to fatal pulmonary fibrosis (PF) [1]. ADinduced lung injury may result from direct toxicity to lung tissues, hypersensitivity to AD, increased oxidative stress, changes in membrane properties, activation of alveolar macrophages, and cytokine release [2]. Several studies investigating the mechanism of AD-induced PF have been reported.…”

Section: Introductionmentioning

confidence: 99%

Loureirin B attenuates amiodarone-induced pulmonary fibrosis by suppression of TGFβ1/Smad2/3 pathway

Ma¹,

Shi²,

Wei³

et al. 2020

Trop. J. Pharm Res

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Purpose: To investigate the therapeutic effect of loureirin B (LB) on amiodarone (AD)-induced pulmonary fibrosis (PF).Methods: Forty-eight male C57BL/6 mice, 8–10 weeks of age, were divided into four groups (n=12). Oral administration of amiodarone hydrochloride (AD) was performed for 4 weeks to induce pulmonary fibrosis. The degree of fibrosis was assessed by Masson staining, while collagen I and α-smooth muscle actin (α-SMA) levels were evaluated by Western blot analysis. ELISA was used to measure the levels of cytokines TNF-α, IL-1β, and IL-6 in bronchoalveolar lavage fluid (BALF) and lung tissue. Levels of p- Smad2, Smad2, p-Smad3 and Smad3 were determined by western blotting.Results: AD treatment increased the collagen levels and expression levels of collagen I and α-smooth muscle actin (α-SMA) in lung tissue and of inflammatory cytokines TNF-α, IL-1β, and IL-6, in both bronchoalveolar lavage fluid (BALF) and lung tissue in a dose-dependent manner (p < 0.01).Furthermore, AD increased the levels of p-Smad2/3. AD-induced increases in collagen I and α-SMA levels were reversed by loureirin B (LB). In addition, LB reduced AD-induced increased levels of the inflammatory cytokines TNF-α, IL-1β, and IL-6 in both bronchoalveolar lavage fluid (BALF) and lung tissue (p < 0.01).Conclusion: These results demonstrate that LB downregulates expression of fibrosis-related proteins and suppresses AD-induced PF. The mechanism responsible for the protective effect of LB on ADinduced PF might involve inhibition of the Smad2/3 pathway. Thus, LB is a potential therapeutic agent for the management of PF. Keywords: Amiodarone, Loureirin B, Pulmonary fibrosis, Smad, Inflammation

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Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics

Shi

Tang

2021

Cell Biol Toxicol

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Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis

Abstract: This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential.

Cited by 6 publications

References 37 publications

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease

Loureirin B attenuates amiodarone-induced pulmonary fibrosis by suppression of TGFβ1/Smad2/3 pathway

Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics

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