Analysis of the inflammatory response induced by rhMMP-12 catalytic domain instilled in mouse airways.
Macrophage elastase (MMP-12) is a metalloproteinase able to degrade extracellular matrix components such as elastin. As many MMPs, MMP-12 is involved in acute and chronic lung injury. However, its role in the inflammatory process of the lung parenchyma is not clearly understood. In this study, we have investigated the effects of airway instillation of rhMMP-12 on inflammatory cell recruitment, cytokine release and gelatinase expression in bronchoalveolar lavage fluid (BALF) or in lung homogenate supernatants in mice. Numbers of total and individual cell types were examined in BALF during the first 72 h following rhMMP-12 instillation. A marked recruitment of neutrophils was observed with a maximum increase at 18 h. This cellular recruitment was associated with a very transient increase in IL-6, TNF-alpha MIP-1alpha, MCP-1 and KC levels and gelatinase expression in BALF and in lung homogenate supernatants. From days 4 to 15, performing the same analyses, we observed an important and stable recruitment of macrophages in BALF in absence of the other studied inflammatory markers. These results demonstrate that rhMMP-12 itself is able to induce an early inflammatory response characterized by neutrophil infiltration, cytokine release and gelatinase activation followed by a later response composed mainly of macrophage recruitment.
Nénan
Soazig
S
Pfizer Global R&D, Fresnes Laboratories, Fresnes, France.
Planquois
Jean-Michel
JM
Berna
Patrick
P
De Mendez
Isabelle
I
Hitier
Simon
S
Shapiro
Steve D
SD
Boichot
Elisabeth
E
Lagente
Vincent
V
Bertrand
Claude P
CP
D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D020134:Catalytic Domain; D002452:Cell Count; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000166:cytology; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology; D011994:Recombinant Proteins / Q000494:pharmacology*
D018925:Chemokines; D016207:Cytokines; D004792:Enzyme Precursors; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12