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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.

Aminopeptidase, preferring phenylalanine-p-nitroanilide as substrate, and proline iminopeptidase, highly-specific for proline-p-nitroanilide, were isolated from cabbage leaves (Brassica oleraceae var. capitata). As pH optima, 7.2−7.5 for aminopeptidase activity and 8.0−8.5 for proline iminopeptidase were determined. Both peptidases were strongly inhibited by p-chloromercuribenzoic acid, heavy metal ions and urea. The molecular weights were determined by gel filtration to be 56 and 204 kDa, respectively. The iminopeptidase was decomposed during SDS electrophoresis to four subunits of 50 kDa. Minor impurities of myrosinase- associated protein (~70 kDa) were found in both preparations. Preliminary data of their amino acid sequences showed similarities to those of aminopeptidases N (family M1) and proline iminopeptidases (family S33).