Hyaluronic acid blocks porcine pancreatic elastase (PPE)-induced bronchoconstriction in sheep.
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 microg) 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.
Scuri
M
M
Division of Pulmonary Disease and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA. mscuri@MSMC.com
Abraham
W M
WM
Botvinnikova
Y
Y
Forteza
R
R
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D001920:Bradykinin / Q000187:drug effects / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D007322:Instillation, Drug; D008970:Molecular Weight; D010196:Pancreatic Elastase / Q000009:adverse effects*; D012756:Sheep; D013552:Swine; D020840:Tissue Kallikreins / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
D000276:Adjuvants, Immunologic; D006820:Hyaluronic Acid; D020840:Tissue Kallikreins; D010196:Pancreatic Elastase; D001920:Bradykinin