The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.
Simler
N R
NR
North West Lung Research Centre, South Manchester University NHS Hospitals Trust, Wythenshawe Hospital, UK.
Howell
D C J
DC
Marshall
R P
RP
Goldsack
N R
NR
Hasleton
P S
PS
Laurent
G J
GJ
Chambers
R C
RC
Egan
J J
JJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001761:Bleomycin; D003094:Collagen / Q000032:analysis; D000068338:Everolimus; D006909:Hydroxyproline / Q000032:analysis; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D009929:Organ Size; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013154:Spleen / Q000033:anatomy & histology / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D001761:Bleomycin; D003094:Collagen; D000068338:Everolimus; D006909:Hydroxyproline; D020123:Sirolimus