Mast cells mediate complement activation after acid aspiration.
A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 but not C4 genetic knockout mice are protected from permeability edema. Using mast cell-deficient mice (W/Wv), we tested the hypothesis that mast cells mediate complement activation after acid aspiration. Tracheostomy tubes were placed in anesthetized mice and 2 mL/kg 0.1 N HCL was instilled in the trachea. After 4 h, extravasation of 125I-albumin was used to calculate lung vascular permeability. The serum alternative complement pathway hemolytic activity was examined, and lung immunohistochemistry was performed. Lung permeability in W/Wv mice was 62% less than that of mast cell sufficient (+/+) animals and similar to +/+ mice treated with the chymase inhibitor chymostatin (65% decrease). Treatment of +/+ mice with D-PRO2,D-TRP(7,9)-Substance P, an antagonist to the neuropeptide substance P, reduced injury by 66%. Serum complement hemolytic activity was intact in injured w/wv mice and +/+ animals treated with chymostatin or dpdt-sp, but was decreased to 65% in the injured untreated +/+ group. Alveolar C3 deposition was intense in injured untreated +/+ mice but absent in the other groups. We interpret these data to indicate that mast cells mediate complement activation, via chymase degranulation, after acid aspiration. This mast cell activity likely is regulated by the release of substance P.
Kyriakides
C
C
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Austen
W G
WG
Wang
Y
Y
Favuzza
J
J
Kobzik
L
L
Moore
F D
FD
Hechtman
H B
HB
D000818:Animals; D053818:Chymases; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D003181:Complement C4 / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D011015:Pneumonia, Aspiration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism
D003176:Complement C3; D003181:Complement C4; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D013373:Substance P; C002101:chymostatin; D012697:Serine Endopeptidases; D053818:Chymases