RESUMO
This study aimed to explore the protective effect of hydrogen and to investigate the underlying mechanism of its preliminary effect on the alveolar epithelial barrier function in septic rats. Forty-five male Sprague-Dawley rats were divided randomly into three groups (N = 15): control [saline injection (intraperitoneal, ip), air drawing; SA], acute lung injury group [lipopolysaccharide (LPS) injection (ip, 15 mg/kg), air drawing; LA], and acute lung injury combined with hydrogen drawing group [LPS injection (ip, 15 mg/kg), 2% hydrogen drawing; LH]. The rats were euthanized after 6 h of treatment, and the extravascular lung water (EVLW), pulmonary alveolar-arterial oxygen pressure (A-aDO2), and respiratory index (RI) of each group were measured. The aquaporin-1 (AQP-1) protein expression in the lung tissues was detected using immunohistochemistry and western blotting, and the correlation between the EVLW and AQP-1 was analyzed. The lung morphology was observed with light and electron microscopy. In the LA group, EVLW (0.87 ± 0.17), A-aDO2 (113.21 ± 13.92), RI (0.65 ± 0.26), and AQP-1 expression increased. Additionally, thickened alveolar walls, significant invasion of inflammatory cells around the vessels, capillary ectasia, hyperemia/hemorrhage in the alveolar space, significantly swollen mitochondria, and increased vacuolar degeneration were observed. A significant negative correlation between AQP-1 expression and EVLW was observed (R2 = 0.8806). Compared with the LA group, EVLW (0.71 ± 0.19), A-aDO2 (132.42 ± 17.39), RI (0.75 ± 0.24), and inflammatory reaction decreased and AQP-1 expression increased in the LH group. The damage to pulmonary epithelial cells improved after hydrogen treatment in rats with sepsis; hydrogen could protect the pulmonary epithelial barrier function by acting on AQP-1.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Aquaporina 1/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Hidrogênio/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Sepse/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Aquaporina 1/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Hidrogênio/uso terapêutico , Masculino , Substâncias Protetoras/farmacologia , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Trypanosoma cruzi is the etiological agent of Chagas disease, an important neglected illness affecting about 12-14 million people in endemic areas of Latin America. The chemotherapy of Chagas disease is quite unsatisfactory mainly due to its poor efficacy especially during the later chronic phase and the considerable well-known side effects. These facts emphasize the need to search for find new drugs. Diamidines and related compounds are minor groove binders of DNA at AT-rich sites and present excellent anti-trypanosomal activity. In the present study, six novel aromatic amidine compounds (arylimidamides and diamidines) were tested in vitro to determine activity against the infective and intracellular stages of T. cruzi, which are responsible for sustaining the infection in the mammalian hosts. In addition, their selectivity and toxicity towards primary cultures of cardiomyocyte were evaluated since these cells represent important targets of infection and inflammation in vivo. The aromatic amidines were active against T. cruzi in vitro, the arylimidamide DB1470 was the most effective compound presenting a submicromolar LD(50) values, good selectivity index, and good activity at 4 °C in the presence of blood constituents. Our results further justify trypanocidal screening assays with these classes of compounds both in vitro and in vivo in experimental models of T. cruzi infection.