Effects on cytokines and histology by treatment with the ACE inhibitor captopril and the antioxidant retinoic acid in the monocrotaline model of experimentally induced lung fibrosis.
Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFbeta, TNFalpha, interleukin 6, and IFN_. TGFbeta was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFN_, and demonstrated the greatest limitation of MCT-induced TNFalpha. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.
Baybutt
Richard C
RC
Dept. of Human Nutrition, Kansas State University, Manhattan, KS 66506, USA. baybutt@humec.ksu.edu
Herndon
Betty L
BL
Umbehr
Joshua
J
Mein
Jonathan
J
Xue
Yuan
Y
Reppert
Sara
S
Van Dillen
Christine
C
Kamal
Robin
R
Halder
Anirudha
A
Molteni
Agostino
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D016207:Cytokines; D014212:Tretinoin; D016686:Monocrotaline; D002216:Captopril