nAChR in the intestinal mucosa
E) cadherin& (RelaFve)expression) 1
80 60 40
Cell)viability)(%)
0 20 100 80 60 40
Cell)viability)(%)
0 50 100 200 300 400 PC>SOD)(U/ml)
0 50 100 200 300 400 PC>SOD)(U/ml)
0
0
0
0 4
3 2 1
Col1a1& (RelaFve)expression) 5
4
2 1 Col1a3& (RelaFve)expression)
3
Cont Cont
Cont Cont
TGF>β1)
(1)ng/ml) TGF>β1)
(1)ng/ml)
TGF>β1)
(5)ng/ml) TGF>β1)
(5)ng/ml)
200 200
200 200 400
400 400
400 +)PC>SOD)
(U/ml) +)PC>SOD)
(U/ml)
+)PC>SOD)
(U/ml) +)PC>SOD)
(U/ml) 6
4 2 Col1a1& (RelaFve)expression)
8 10 12
E)cadherin& (RelaFve)expression) 1
0.5 1.5
第
4
節BLM
肺線維症に対するPC-SOD
の改善効果に対するカタラーゼ同時投与の効果第
1
節で述べたとおり，PC-SOD のBLM
肺線維症に対する用量依存性のベルシェイプ現象は他の報 告においても見られている123, 124．この高用量のPC-SOD
がBLM
の効果に対して無効であったことに対 する一つの説明として，カタラーゼと比較してSOD
の活性が相対的に高くなることによる過酸化水素 の集積が考えられる．我々はこれまでに，他の実験動物モデルにおいてこの考えを支持する知見を見出している．すなわち，
DSS
腸炎に対して高用量のPC-SOD
は無効であったが，カタラーゼを同時に投与 することによって高用量のPC-SOD
により腸炎抑制効果が得られた126．この考えに基づき，BLMを投 与した実験動物においても高用量のPC-SOD
とカタラーゼの同時投与の検討を行った．その結果，PC-SOD 30 kU/kg
とカタラーゼ (1.5–6 kU/ kg) を同時に静脈内投与することによりBLM
により誘導さ れる炎症反応（BALF内の炎症性細胞の増加）が改善されたが，カタラーゼの非存在下ではその効果は見られなかった (Fig. 23A)．また，カタラーゼ単独の投与は
BLM
により誘導される炎症反応に対して 有意な影響を与えなかった (Fig. 23A)．次に，高用量
PC-SOD
とカタラーゼの同時投与の効果をBLM
肺線維症の他の側面から検討を行った．BLM
により誘導された肺傷害とこれらの傷害部位への炎症性細胞の浸潤は高用量PC-SOD
とカタラー ゼの同時投与により明らかに抑制された．しかしながら，カタラーゼあるいは高用量PC-SOD
の単独投 与はこれらの改善効果を示さなかった (Fig. 23B)．コラーゲンの沈着およびヒドロキシプロリン量の増加もまた高用量
PC-SOD
とカタラーゼの同時投与により明らかに抑制された (Fig. 23C, D)．また，この 検討においてもカタラーゼあるいは高用量PC-SOD
の単独投与はこれらの改善効果を示さなかった(Fig. 23C, D)．さらに，肺の過酸化水素量を直接測定することによりこの考えについて検証を行った．
その結果，
Table 8
に示す通り，高用量PC-SOD
（30 kU/kg）の投与は肺の過酸化水素量を上昇させたが，低用量
PC-SOD (1.5 kU/kg)
においてはこの上昇は見られなかった．これらFig.23
とTable 8
の結果は，カタラーゼによる高用量
PC-SOD
のBLM
肺線維症に対する効果の回復はSOD
活性が相対的に高まるこFig. 23. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflammatory response and fibrosis.
Mice were treated with bleomycin and PC-SOD, and the inflammatory response (A) and pulmonary fibrosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intravenously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (B and C). Values are means ± SE.
*or
#P<0.05;
**or
##P<0.01.
EMT was induced. PC-SOD did not affect these TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org
A
0 Total(cells( (×(105(cells)
1 2 3 4 5 6
01 2 3 4 5 6
0 1 2 3 0 0.5 1 1.5
Alveolar( macrophages( (×(105(cells) Lymphocytes( (×(104(cells)Neutrophils( (×(104(cells)
BLM((5)(alone +(PC((30)
+(PC((30)(+(Cat((1.5) +(PC((30)(+(Cat((3) +(PC((30)(+(Cat((6)
*((v.s.(BLM((5)(alone)(
#((v.s.(+(PC((30))(
+(Cat((6)
B
BLM((5)(alone +(PC((30)+(Cat((6) +(PC((30)(+(Cat((6)
C
BLM((5)(alone +(PC((30)+(Cat((6) +(PC((30)(+(Cat((6) EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org
EMT was induced. PC-SOD did not affect these TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org EMT was induced. PC-SOD did not affect these
TGF-!1-dependent alterations of mRNA expression (Fig. 3C). These results suggest that PC-SOD does not affect the TGF-!1-induced collagen synthesis and EMT.
Effect of simultaneous administration of catalase on the ameliorative effect of PC-SOD against bleomycin-induced pul-monary fibrosis.As described in the introduction, a bell-shaped dose-response profile of PC-SOD against bleomycin-induced pulmonary fibrosis has also been observed in other studies (44, 50). One possible explanation for the ineffectiveness of high doses of PC-SOD to combat the effects of bleomycin is the accumulation of hydrogen peroxide due to the relatively higher activity of SOD compared with catalase. We recently found evidence to support this notion in another animal model;
simultaneous administration of catalase restored the ineffec-tiveness of higher doses of PC-SOD to combat dextran sulfate sodium-induced colitis, an animal model of UC (19). On this basis, we tested here the effect of concurrent administration of
catalase on the activity of a high dose of PC-SOD in bleomy-cin-treated animals. Administration of 30 kU/kg PC-SOD im-proved the bleomycin-induced inflammatory response (in-crease in inflammatory cells in BALF) in the presence of the concurrent intravenous administration of catalase (1.5– 6 kU/
kg), but not in its absence (Fig. 4A). Administration of catalase alone did not significantly affect the bleomycinduced in-flammatory response (Fig. 4A).
We next examined the effect of simultaneous administration of catalase and high doses of PC-SOD on other aspects of bleomycin-induced pulmonary fibrosis. Bleomycin-induced pulmonary damage and infiltration of inflammatory cells into these regions were clearly suppressed by the simulta-neous administration of catalase and a high dose of PC-SOD; however, treatment with either catalase or PC-SOD alone did not bring about such ameliorative effects (Fig.
4B). Collagen deposition and an increase in hydroxyproline levels were also clearly suppressed by the simultaneous
Fig. 4. Effect of concurrent administration of catalase on the ameliorative effect of PC-SOD on the bleomycin-induced inflamma-tory response and fibrosis. Mice were treated with bleomycin and PC-SOD, and the in-flammatory response (A) and pulmonary fi-brosis (B–D) were assessed as described in the legends of Figs. 1 and 2. The indicated dose of catalase (Cat) (kU/kg) was intrave-nously administered once per day for 3 days (A) or 14 days (B–D). Similar results were obtained for at least 3 sections (BandC).
Values are means"SE. * or #P#0.05; **
or ##P#0.01.
L354 PC-SOD AND BLEOMYCIN-INDUCED FIBROSIS
AJP-Lung Cell Mol Physiol•VOL 298 • MARCH 2010 •www.ajplung.org
D
Hydroxyproline- (µg/right-lung) 0 20 40 60
BLM-(5)-alone control +-PC-(30)
+-Cat-(6) +-PC-(30)-+-Cat-(6)
*-(v.s.-BLM-(5)-alone)-