Enhancement of ovalbumin-induced pulmonary eosinophilia by intranasal administration of alpha1-proteinase inhibitor type 2 antisense oligonucleotides.
To identify asthma-susceptibility genes, we did proteome analyses of the lung from control and ovalbumin-sensitized BALB/c mice. Among the 6 up-regulated proteins is alpha(1)-protease inhibitor (alpha(1)-PI) type 2, which is a member of the serine protease inhibitor superfamily of protease inhibitors that participate in a variety of physiological functions, including extracellular matrix remodeling and inflammation. The up-regulated expression of alpha(1)-PI type 2 was confirmed by real-time PCR. Then we examined mRNA expression of five members of the alpha(1)-PI family genes (alpha(1)-PI types 1-5) in several organs of BALB/c mice and found that in addition to the liver, all the organs tested also expressed different isoforms of alpha(1)-PI in a tissue-specific manner, albeit to a lesser extent compared with the liver. When a similar study was performed with C57BL/6 mice, which have been shown to be more susceptible to ovalbumin-induced asthma than BALB/c mice, a pair of remarkable differences between the mouse strains were revealed: (1) the magnitude of alpha(1)-PI type 2 mRNA in all the organs was much higher in BALB/c than in C57BL/6 mice and (2) alpha(1)-PI type 2 is the only isoform expressed in the lung of BALB/c, but not of C57BL/c mice. Using the antisense oligonucleotide technology to specifically down-regulate expression of alpha(1)-PI type 2, we demonstrated that pulmonary infiltration of eosinophils was significantly increased by intranasal administration of alpha(1)-PI type 2 antisense oligonucleotides in OVA-sensitized mice, suggesting that alpha(1)-PI type 2 may suppress the progress of asthma, probably by acting on neutrophil elastase, which can produce many of the pathological features of asthma.
Sung
Ha-Na
HN
Department of Biology, Changwon National University,Changwon, Kyungnam, South Korea.
Jeon
Chang-Hwan
CH
Gill
Byoung-Chul
BC
Kim
Hye-Rin
HR
Cheong
Sun-Woo
SW
Park
Joo-Hung
JH
D000281:Administration, Intranasal; D000818:Animals; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D009928:Organ Specificity; D010047:Ovalbumin / Q000276:immunology; D040901:Proteomics; D011657:Pulmonary Eosinophilia / Q000276:immunology* / Q000628:therapy; D013045:Species Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D000515:alpha 1-Antitrypsin; D010047:Ovalbumin