Can LASSBio 596 and dexamethasone treat acute lung and liver inflammation induced by microcystin-LR?

Abstract

The treatment of microcystin-LR (MCYST-LR)-induced lung inflammation has never been reported. Hence, LASSBio 596, an anti-inflammatory drug candidate, designed as symbiotic agent that modulates TNF-alpha levels and inhibits phosphodiesterase types 4 and 5, or dexamethasone were tested in this condition. Swiss mice were intraperitoneally (i.p.) injected with 60 microl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 micrg/kg). 6 h later they were treated (i.p.) with saline (TOX), LASSBio 596 (10 mg/kg, L596), or dexamethasone (1 mg/kg, 0.1 mL, DEXA). 8 h after MCYST-LR injection, pulmonary mechanics were determined, and lungs and livers prepared for histopathology, biochemical analysis and quantification of MCYST-LR. TOX showed significantly higher lung impedance than CTRL and L596, which were similar. DEXA could only partially block the mechanical alterations. In both TOX and DEXA alveolar collapse and inflammatory cell influx were higher than in CTRL and L596, being LASSBio 596 more effective than dexamethasone. TOX showed oxidative stress that was not present in CTRL and L596, while DEXA was partially efficient. MCYST-LR was detected in the livers of all mice receiving MCYST-LR and no recovery was apparent. In conclusion, LASSBio 596 was more efficient than dexamethasone in reducing the pulmonary functional impairment induced by MCYST-LR.

Repeated intranasal exposure to microcystin-LR affects lungs but not nasal epithelium in mice

“…This inhibition results in hyperphosphorylation of cytoskeleton proteins, consequently discontinuing some cellular processes like arrangement of the cytoskeleton subunits and cellecell adhesion (Frangez et al, 2003). Nevertheless, another parallel mechanism has been already demonstrated, which also explains MC-LR toxicity: the redox system imbalance that can end up in inflammation (Nobre et al, 2003;Carvalho et al, 2010;Mattos et al, 2014). Indeed, the toxin intranasally administered to our mice could eventually reach the lung and trigger the inflammatory response observed.…”

“…injection of MC-LR (Picanço et al, 2004;Soares et al, 2007;Carvalho et al, 2010;Casquilho et al, 2011). However, the functional and histological assessments following a sub-chronic exposure to low doses are still poorly documented in the literature.…”

Potential Inhibitory Effect of LASSBio-596, a New Thalidomide Hybrid, on Inflammatory Corneal Angiogenesis in Rabbits

“…Moreover, LASSBio-596 was reported to effectively prevent mechanical and morphometric changes in the lung, and it was observed to block fibroproliferation in a BALB/c mouse model of asthma [12]. It was also reported that LASSBio-596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by microcystins [25,26]. Because of this important anti-inflammatory action, we begin the study of LASSBio-596 in inflammatory angiogenesis, believing in its potential antiangiogenic effect.…”

Respiratory and Systemic Effects of LASSBio596 Plus Surfactant in Experimental Acute Respiratory Distress Syndrome

“…Additionally, all these therapies reduced liver dysfunction. Similarly, in experimental lung injury induced by endotoxin [17] and microcystin-LR [18,19], i.p. administration of LASSBio596 has been shown to reduce pulmonary functional impairment and TNF-α.…”

“…Our group reported the use of LASSBio596 to treat ARDS induced by E.coli lipopolysaccharide [17]. This compound effectively reduced pulmonary inflammation in experimental lung injury induced by endotoxin [17] and microcystin-LR [18,19], and elastase induced emphysema [20].…”