Abstract
Emphysema is an intractable pulmonary disease characterized by an inflammatory process of the airways and lung parenchyma and ongoing remodeling process in an attempt to restore lung structure. There is no effective drug therapy that regenerates lung tissue or prevents the progression of emphysema; current treatment is aimed at symptomatic relief. We hypothesized that LASSBio-596, a molecule with potent anti-inflammatory and immunomodulatory effects, might reduce pulmonary inflammation and remodeling and thus improve lung function in experimental emphysema. Emphysema was induced in BALB/c mice by intratracheal administration of porcine pancreatic elastase (0.1 IU) once weekly during 4 weeks. A control group received saline using the same protocol. After the last instillation of saline or elastase, dimethyl sulfoxide, or LASSBio-596 were administered intraperitoneally, once daily for 8 days. After 24 h, in elastase-induced emphysema animals, LASSBio-596 yielded: (1) decreased mean linear intercept, hyperinflation and collagen fiber content, (2) increased elastic fiber content, (3) reduced number of M1 macrophages, (4) decreased tumor necrosis factor-α, interleukin-1β, interleukin-6, and transforming growth factor-β protein levels in lung tissue, and increased vascular endothelial growth factor. These changes resulted in increased static lung elastance. In conclusion, LASSBio-596 therapy reduced lung inflammation, airspace enlargement, and small airway wall remodeling, thus improving lung function, in this animal model of elastase-induced emphysema.
Highlights
Emphysema, defined as irreversible destruction of the alveoli, is associated with an inflammatory process of the airways and lung parenchyma (Newell, 2008) and an ongoing remodeling process in an attempt to restore lung structure (Papaioannou et al, 2010)
LASSBio-596 is an achiral molecule in the carbamoyl-benzoic acid class that was designed as a symbiotic agent from the hybridization of prototypes originating from thalidomide, arylsulfonamide, and sildenafil (Lima et al, 2002; Rocco et al, 2010)
The therapeutic potential of LASSBio-596 has been studied in experimental models of acute lung inflammation induced by Escherichia coli lipopolysaccharide (Rocco et al, 2003), microcystin-LR (Carvalho et al, 2010), and chronic allergic inflammation (Campos et al, 2006); it has been found to act mainly on inflammatory processes, improving pulmonary function
Summary
Emphysema, defined as irreversible destruction of the alveoli, is associated with an inflammatory process of the airways and lung parenchyma (Newell, 2008) and an ongoing remodeling process in an attempt to restore lung structure (Papaioannou et al, 2010). Respiratory effects of LASSBio-596 in experimental emphysema symptomatic relief. One potential therapeutic approach for emphysema is decreasing the chronic inflammation and fibrogenesis associated with induction of lung repair and regeneration. The therapeutic potential of LASSBio-596 has been studied in experimental models of acute lung inflammation induced by Escherichia coli lipopolysaccharide (Rocco et al, 2003), microcystin-LR (Carvalho et al, 2010), and chronic allergic inflammation (Campos et al, 2006); it has been found to act mainly on inflammatory processes, improving pulmonary function. LASSBio-596 is not associated with relevant side effects, unlike corticosteroids, which are commonly used in emphysema (Calverley, 2014). We hypothesized that, in an elastase-induced emphysema model, LASSBio-596 therapy might act on lung inflammation and remodeling as well as stimulate elastogenesis
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