Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice.
The cells/proteases responsible for the development of smoke-induced emphysema is an area of intense investigation. Mice with knockout of macrophage metalloelastase genes (MME(-/-)) do not develop emphysema after smoke exposure, but we also observed that neutrophils (PMN) in lavage appeared to be a requirement for acute connective tissue breakdown. In this study we exposed mice to cigarette smoke and examined lavage PMN, macrophages (MAC), desmosine (DES, a measure of elastin breakdown) and hydroxyproline (HP, a measure of collagen breakdown) 24 h afterwards. MME(+/+) mice exposed to smoke showed elevations in PMN, DES, and HP, but no elevations were seen in MME-deficient mice. Both PMN influx and increased levels of DES/HP could be restored by administering MAC from MME(+/+) mice to MME-deficient mice and then exposing them to smoke. RS113456, a metalloprotease inhibitor, also prevented PMN influx and connective tissue breakdown. Western blots against mouse alpha(1)-antitrypsin (alpha(1)AT) showed that alpha(1)AT was not protected in MME-deficient mice, nor by administration of RS113456. We conclude that, in mice, acute smoke-induced connective tissue breakdown, the precursor to emphysema, requires both PMN and MME, that PMN influx appears to be secondary to MAC activation, and that this process initially does not involve protection of alpha(1)AT from metalloprotease attack.
Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. achurg@interchange.ubc.ca
Andrew
A
Churg
Katalin
K
Zay
Selena
S
Shay
Changshi
C
Xie
Steven D
SD
Shapiro
Robert
R
Hendricks
Joanne L
JL
Wright
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology; D003895:Desmosine / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D004646:Emphysema / Q000209:etiology* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006909:Hydroxyproline / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D004791:Enzyme Inhibitors; D011714:Pyrans; C113899:RS 113456; D014028:Tobacco Smoke Pollution; D000515:alpha 1-Antitrypsin; D003895:Desmosine; D003094:Collagen; D004549:Elastin; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12; D006909:Hydroxyproline