The influence of 5-lipoxygenase on cigarette smoke-induced emphysema in mice.
BACKGROUND
Pulmonary emphysema is characterized by the loss of lung architecture. Our hypothesis is that the inhibition of 5-lipoxygenase (5-LO) production may be an important strategy to reduce inflammation, oxidative stress, and metalloproteinases in lung tissue resulting from cigarette smoke (CS)-induced emphysema.


METHODS
5-LO knockout (129S2-Alox5(tm1Fun)/J) and wild-type (WT) mice (129S2/SvPas) were exposed to CS for 60days. Mice exposed to ambient air were used as Controls. Oxidative, inflammatory, and proteolytic markers were analyzed.


RESULTS
The alveolar diameter was decreased in CS 5-LO(-/-) mice when compared with the WT CS group. The CS exposure resulted in less pronounced pulmonary inflammation in the CS 5-LO(-/-) group. The CS 5-LO(-/-) group showed leukotriene B4 values comparable to those of the Control group. The expression of MMP-9 was decreased in the CS 5-LO(-/-) group when compared with the CS WT group. The expression of superoxide dismutase, catalase, and glutathione peroxidase were decreased in the CS 5-LO(-/-) group when compared with the Control group. The protein expression of nuclear factor (erythroid-derived 2)-like 2 was reduced in the CS 5-LO(-/-) group when compared to the CS WT group.


CONCLUSIONS
In conclusion, we show for the first time that 5-LO deficiency protects 129S2 mice against emphysema caused by CS. We suggest that the main mechanism of pathogenesis in this model involves the imbalance between proteases and antiproteases, particularly the association between MMP-9 and TIMP-1. General significance This study demonstrates the influence of 5-LO mediated oxidative stress, inflammation, and proteolytic markers in CS exposed mice.
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Emanuel
E
Kennedy-Feitosa
Rômulo Fonseca Santos
RF
Pinto
Karla Maria Pereira
KM
Pires
Ana Paula Teixeira
AP
Monteiro
Mariana Nascimento
MN
Machado
Juliana Carvalho
JC
Santos
Marcelo Lima
ML
Ribeiro
Walter Araújo
WA
Zin
Cláudio Azevedo
CA
Canetti
Bruna
B
Romana-Souza
Luís Cristóvão
LC
Porto
Samuel Santos
SS
Valenca
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011014:Pneumonia / Q000235:genetics / Q000517:prevention & control*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012906:Smoke; D019715:Tissue Inhibitor of Metalloproteinase-1; D001094:Arachidonate 5-Lipoxygenase; D020780:Matrix Metalloproteinase 9
5-lipoxygenase; Cigarette smoke; Emphysema; MMP-9; Oxidative stress