TY - JOUR
T1 - Hyaluronic acid blocks porcine pancreatic elastase (PPE)-induced bronchoconstriction in sheep
AU - Scuri, Mario
AU - Abraham, William M.
AU - Botvinnikova, Yelena
AU - Forteza, Rosanna
PY - 2001/11/15
Y1 - 2001/11/15
N2 - We previously showed that inhaled porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep via a bradykinin-mediated mechanism. Hyaluronic acid (HA), in vitro, binds and inactivates airway tissue kallikrein (TK), the enzyme responsible for kinin generation. Therefore, we hypothesized that in vivo, HA should prevent PPE-induced bronchoconstriction by binding and inactivating TK. To test this, we measured pulmonary resistance (RL) in allergic sheep before and after inhalation of PPE alone (500 μg) and after pretreatment with either inhaled HA at 70 kD, designated low molecular weight (LMW)-HA or 200 kD, designated high molecular weight (HMW)-HA at different concentrations. Inhaled PPE increased RL 147 ± 8% over baseline values and this effect was associated with a 111 ± 28% increase in bronchoalveolar lavage fluid (BALF) TK activity. HA blocked the PPE-induced bronchoconstriction and the increase in BALF TK activity in a dose-dependent and molecular weight-dependent fashion. HA alone had no effect on RL. Instillation of PPE in the lung increased kinin concentrations in BALF, a result consistent with the PPE-induced increase in BALF TK activity. Our findings show that HA blocks PPE-induced bronchoconstriction in a dose-dependent and molecular weight-dependent fashion by a mechanism that may, in part, be related to inhibition of TK activity and the formation of kinins.
AB - We previously showed that inhaled porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep via a bradykinin-mediated mechanism. Hyaluronic acid (HA), in vitro, binds and inactivates airway tissue kallikrein (TK), the enzyme responsible for kinin generation. Therefore, we hypothesized that in vivo, HA should prevent PPE-induced bronchoconstriction by binding and inactivating TK. To test this, we measured pulmonary resistance (RL) in allergic sheep before and after inhalation of PPE alone (500 μg) and after pretreatment with either inhaled HA at 70 kD, designated low molecular weight (LMW)-HA or 200 kD, designated high molecular weight (HMW)-HA at different concentrations. Inhaled PPE increased RL 147 ± 8% over baseline values and this effect was associated with a 111 ± 28% increase in bronchoalveolar lavage fluid (BALF) TK activity. HA blocked the PPE-induced bronchoconstriction and the increase in BALF TK activity in a dose-dependent and molecular weight-dependent fashion. HA alone had no effect on RL. Instillation of PPE in the lung increased kinin concentrations in BALF, a result consistent with the PPE-induced increase in BALF TK activity. Our findings show that HA blocks PPE-induced bronchoconstriction in a dose-dependent and molecular weight-dependent fashion by a mechanism that may, in part, be related to inhibition of TK activity and the formation of kinins.
KW - Asthma
KW - Bradykinin
KW - Hyaluronan
KW - Pancreatic elastase
KW - Polysaccharides
KW - Serine proteases
UR - http://www.scopus.com/inward/record.url?scp=0035891608&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035891608&partnerID=8YFLogxK
U2 - 10.1164/ajrccm.164.10.2011115
DO - 10.1164/ajrccm.164.10.2011115
M3 - Article
C2 - 11734436
AN - SCOPUS:0035891608
VL - 164
SP - 1855
EP - 1859
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 10 I
ER -