A novel pharmacological approach for paraquat poisoning in rat and A549 cell line using ambroxol, a lung surfactant synthesis inducer.
Paraquat (PQ) is a widely used herbicide that causes acute adult respiratory distress syndrome (ARDS) and chronic lung damage (diffuse fibrosis). One of the earliest biochemical effects induced by PQ is damage to type II pneumocytes with consequent depletion of surfactant. With the aim of counteracting the toxic effects of PQ, a series of investigations were performed into the possible protective effect of the drug ambroxol, which induces the synthesis of surfactant in lung alveolar type II cells. The number of survivors and survival time of rats treated ip with 35 mg PQ/kg was significantly increased by 3 days of ambroxol pretreatment and by ambroxol treatment 30 min or 2 hr after PQ. Total phospholipid content in lung and bronchoalveolar lavage fluid (BALF) was significantly reduced 30 hr after treatment with PQ alone. The association of ambroxol with PQ significantly antagonized this reduction. In BALF the ratio between palmitic acid and stearic acid concentrations was significantly lower in animals treated with PQ alone but was returned to normal by the association with ambroxol. The cell line A549, exposed in vitro to PQ concentrations from 0.5 x 10(-4) to 2 x 10(-3) M, showed a significant dose-dependent loss of viability. Cells pretreated with ambroxol (10 mg/ml) were more resistant to PQ and their viability started to decrease significantly only from a PQ concentration of 0.8 x 10(-3) M. Membrane microviscosity was measured on the same cells. Cells treated with PQ alone showed a reduction of membrane microviscosity, which was significantly counteracted by ambroxol pretreatment. The curves of modification of membrane microviscosity of cells treated with PQ and with ambroxol plus PQ paralleled those of cell viability, indicating that the stimulation of surfactant synthesis in vitro may be a prerequisite for counteracting some of the early effects of PQ.
Salmona
M
M
Laboratory for Enzyme Research, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Donnini
M
M
Perin
L
L
Diomede
L
L
Romano
M
M
Marini
M G
MG
Tacconi
M T
MT
Luisetti
M
M
D000230:Adenocarcinoma; D000551:Ambroxol / Q000627:therapeutic use*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007928:Lethal Dose 50; D008168:Lung / Q000737:chemistry / Q000187:drug effects; D008175:Lung Neoplasms; D008297:Male; D010269:Paraquat / Q000506:poisoning* / Q000633:toxicity; D010743:Phospholipids / Q000032:analysis; D011041:Poisoning / Q000517:prevention & control; D011506:Proteins / Q000032:analysis; D011663:Pulmonary Surfactants / Q000096:biosynthesis*; D051381:Rats; D014407:Tumor Cells, Cultured; D014783:Viscosity / Q000187:drug effects
D010743:Phospholipids; D011506:Proteins; D011663:Pulmonary Surfactants; D000551:Ambroxol; D010269:Paraquat