Suppression of perfluoroisobutylene induced acute lung injury by pretreatment with pyrrolidine dithiocarbamate.
Perfluoroisobutylene (PFIB) is produced as a main by-product in large quantities by the fluoropolymer industry. As a highly toxic compound, even the case of brief inhalation of PFIB can result in acute lung injury (ALI), pulmonary edema and even death. To test for any preventive or therapeutic effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB activation inhibitor, against PFIB inhalation-induced ALI, mice were exposed in a flow-past exposure system to PFIB and the prophylactic and therapeutic effects of PDTC were studied. The inhibitory effects of PDTC on ALI, the activation of NF-kappaB, as well as the expression of cytokines (IL-1beta and IL-8) after PFIB exposure were evaluated. The results demonstrated that pretreatment with PDTC (120 mg/kg, 30 min before PFIB exposure) could significantly lower the lung coefficient (wet lung-to-body weight ratio, dry lung-to-body weight ratio, water content in the lung, and lung wet-to-dry weight ratio) and protein content in bronchoalveolar lavage fluid (BALF), but no effects of PDTC were found when PDTC was treated after PFIB inhalation, suggesting a preventative effect rather than a therapeutic effect of PDTC. Furthermore, the above preventative effects of PDTC (when given at 30 min before PFIB exposure) on PFIB-induced lung injury were achieved in a dose-dependent manner. In support of these preventive effects of PDTC, our toxicological studies demonstrated that PFIB-inhalation induced a quick activation of NF-kappaB (0.5 h post PFIB exposure) and expression of IL-1beta and IL-8 (0.5 h and 1 h post PFIB exposure, respectively). Pretreatment with PDTC (120 mg/kg, 30 min before PFIB exposure) resulted in a significant inhibitive effect on the activation of NF-kappaB (0.5 h post PFIB exposure) and expression of IL-1beta and IL-8 (1 h post PFIB exposure). The mortality, the extent of lung injury of the mice indexed by lung coefficients, the content of total protein and albumin in BALF, as well as the lung histopathologic changes, were dramatically alleviated in PFIB exposure after pretreatment with PDTC, clearly suggesting that PDTC has a prophylactic role against PFIB inhalation-induced ALI, and that NF-kappaB activation might play a central role in initiating an acute inflammatory response and in causing injury to the lungs after PFIB inhalation.
Zhao
Jian
J
Beijing Institute of Pharmacology and Toxicology, the China PLA, PR, China.
Shao
Zhihua
Z
Zhang
Xigang
X
Ding
Rigao
R
Xu
Jin
J
Ruan
Jinxiu
J
Zhang
Xiancheng
X
Wang
Hemei
H
Sun
Xiaohong
X
Huang
Chunqian
C
D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005466:Fluorocarbons / Q000008:administration & dosage / Q000633:toxicity*; D008171:Lung Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*
D000975:Antioxidants; D005466:Fluorocarbons; D011759:Pyrrolidines; D013859:Thiocarbamates; C016648:perfluoroisobutylene; C020972:pyrrolidine dithiocarbamic acid