Development of chronic lung injury and pulmonary fibrosis in mice following acute exposure to nitrogen mustard

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

“…We analyzed the ability of the HSP90 inhibitor AUY-922, to inhibit the expression of two pro-fibrotic signaling biomarkers: the activated (phosphorylated) form of extracellular signal-regulated kinase (MAPK/ERK) and of HSP90 ( Figure 7 and Figure 8 ). As we previously reported, instillation of mechlorethamine hydrochloride increases the expression of p-ERK at 4, 10 and 30 days post-exposure [ 18 ]. NM also activates HSP90 (P-HSP90) by phosphorylating a tyrosine in position 300, at 30 days post-exposure.…”

“…We analyzed collagen type I, elastin and fibronectin, key components of the lung extracellular matrix, involved in the maintenance of lung morphology and function. NM exposure in mice has been previously related to increased expression of collagen type I, fibronectin and elastin [ 18 ]. Treatment with 1 mg/kg 2×/week AUY-922 did not statistically reduce collagen type I deposition and mRNA expression ( Figure 4 a,b), however when AUY-922 was employed at the higher dose and frequency (2 mg/kg 3×/week) a significant reduction was observed in collagen, either analyzed by Western blotting ( p < 0.01) or real-time qPCR ( p < 0.05) ( Figure 4 c,d).…”

“…Here, we show how the administration of AUY-922 2 mg/kg 3 times per week significantly reduced the rate of weight loss compared to mice instilled with NM and treated with saline ( Figure 1 ). Models of bleomycin-induced pulmonary fibrosis showed a persistent inflammatory process that lasts for at least 28 days post-exposure [ 22 , 23 , 24 ] and NM-instilled mice, similarly, displayed a strong alveolar inflammation that persists for at least 30 days [ 18 ]. We hypothesized that the inhibition of HSP90 by AUY-922 could suppress the persistent inflammatory process in the lung and prevent the development of NM-induced pulmonary fibrosis.…”

“…We previously observed visible perivascular and peribronchial collagen deposition, substitution of lung parenchyma with a fibrotic scar and narrowing of bronchial and alveolar spaces by the surrounding collagen. TGF-β also showed significant rise at 10 and 30 days after NM instillation [ 18 ]. Accordingly, in this study, mice exposed to NM exhibited increased collagen levels as analyzed by Masson’s Trichrome histological staining, real-time PCR and Western blotting.…”

“…We recently reported that a single exposure of mice to mechlorethamine hydrochloride, induces chronic lung injury and pulmonary fibrosis, thus representing a suitable animal model to study the long-term effects of NM on the lower respiratory tract and its possible countermeasures [ 18 ]. Ten days after intratracheal instillation of NM, mice exhibit progressive deposition of collagen and extracellular matrix, which correlates with HSP90 activation (P-HSP90) and culminates at 30 days post-exposure in an overall aberrant destruction of parenchymal architecture and scar tissue formation.…”