Protective effects of phosphodiesterase inhibitors on lung function and remodeling in a murine model of chronic asthma.
The aim of the present study was to compare the efficacy of a novel phosphodiesterase 4 and 5 inhibitor, LASSBio596, with that of dexamethasone in a murine model of chronic asthma. Lung mechanics (airway resistance, viscoelastic pressure, and static elastance), histology, and airway and lung parenchyma remodeling (quantitative analysis of collagen and elastic fiber) were analyzed. Thirty-three BALB/c mice were randomly assigned to four groups. In the asthma group (N = 9), mice were immunized with 10 microg ovalbumin (OVA, ip) on 7 alternate days, and after day 40 they were challenged with three intratracheal instillations of 20 microg OVA at 3-day intervals. Control mice (N = 8) received saline under the same protocol. In the dexamethasone (N = 8) and LASSBio596 (N = 8) groups, the animals of the asthma group were treated with 1 mg/kg dexamethasone disodium phosphate (0.1 mL, ip) or 10 mg/kg LASSBio596 dissolved in dimethyl sulfoxide (0.2 mL, ip) 24 h before the first intratracheal instillation of OVA, for 8 days. Airway resistance, viscoelastic pressure and static elastance increased significantly in the asthma group (77, 56, and 76%, respectively) compared to the control group. The asthma group presented more intense alveolar collapse, bronchoconstriction, and eosinophil and neutrophil infiltration than the control group. Both LASSBio596 and dexamethasone inhibited the changes in lung mechanics, tissue cellularity, bronchoconstriction, as well as airway and lung parenchyma remodeling. In conclusion, LASSBio596 at a dose of 10 mg/kg effectively prevented lung mechanical and morphometrical changes and had the potential to block fibroproliferation in a BALB/c mouse model of asthma.
Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Rio de Janeiro, RJ, Brazil.
H S
HS
Campos
D G
DG
Xisto
M B G
MB
Oliveira
I
I
Teixeira
E M
EM
Negri
T
T
Mauad
D
D
Carnielli
L M
LM
Lima
E J
EJ
Barreiro
D S
DS
Faffe
W A
WA
Zin
J R
JR
Lapa e Silva
P R M
PR
Rocco
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010795:Phthalic Acids; D010797:Phthalimides / Q000494:pharmacology*; D011897:Random Allocation; D012129:Respiratory Function Tests; D015656:Respiratory Mechanics / Q000187:drug effects*; D013449:Sulfonamides
C514420:LASSBIO596; D010726:Phosphodiesterase Inhibitors; D010795:Phthalic Acids; D010797:Phthalimides; D013449:Sulfonamides; D003907:Dexamethasone