Acute exposure of mice to hydrochloric acid leads to the development of chronic lung injury and pulmonary fibrosis

Маринова

et al. 2020

IJMS

Self Cite

Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-β, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Маринова

et al. 2020

IJMS

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“…In the bleomycin-induced mouse model, BALF and serum displayed high levels of HSP90α and this increase was related to fibrosis [66]. Activated HSP90, phospho-HSP90, was elevated in lung tissue of mice with hydrochloric acid (HCl)-induced pulmonary fibrosis at 10 and 30 days after acid instillation, compared to controls [68]. HSP90 tyrosine phosphorylation induced by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors was reported to increase its association with endothelial nitric oxide (eNOS) [78], a marker for pulmonary hypertension and pulmonary fibrosis [79].…”

Section: Modulation Of Hsp90 By Molecular Inhibitorsmentioning

confidence: 99%

HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF)

Gregory

et al. 2020

IJMS

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Idiopathic Pulmonary fibrosis (IPF) is a catastrophic disease with poor outcomes and limited pharmacological approaches. Heat shock protein 90 (HSP90) has been recently involved in the wound-healing pathological response that leads to collagen deposition in patients with IPF and its inhibition represents an exciting drug target against the development of pulmonary fibrosis. Under physiological conditions, HSP90 guarantees proteostasis through the refolding of damaged proteins and the degradation of irreversibly damaged ones. Additionally, its inhibition, by specific HSP90 inhibitors (e.g., 17 AAG, 17 DAG, and AUY-922) has proven beneficial in different preclinical models of human disease. HSP90 inhibition modulates a complex subset of kinases and interferes with intracellular signaling pathways and proteome regulation. In this review, we evaluated the current evidence and rationale for the use of HSP90 inhibitors in the treatment of pulmonary fibrosis, discussed the intracellular pathways involved, described the limitations of the current understanding and provided insights for future research.

“…To investigate gender-related differences in chemically induced pulmonary fibrosis, we intratracheally instilled male and female mice with either 2 μL/g body weight of 0.1 N hydrochloric acid (HCl) or 0.625 mg/kg body weight mechlorethamine, a nitrogen mustard alkilant. As we have published, these treatments provoke the development of acute alveolar inflammation, chronic lung injury, and pulmonary fibrosis, which last for at least 30 days [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, human exposure to HCl or NM has been related to both acute intoxication and chronic lung disease [ 17 ]. Importantly, NM induces pulmonary fibrosis in mice without evidence of bronchiolitis obliterans syndrome, which is observed with the instillation of sulfur mustards, but it is not typically observed as a clinical characteristic of IPF [ 14 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-Related Differences in Murine Models of Chemically Induced Pulmonary Fibrosis

Dimitropoulou

et al. 2021

IJMS

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We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male–female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.