Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice
Identifieur interne : 000E03 ( Pmc/Checkpoint ); précédent : 000E02; suivant : 000E04Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice
Auteurs : Noriyo Nagata ; Naoko Iwata ; Hideki Hasegawa ; Shuetsu Fukushi ; Ayako Harashima ; Yuko Sato ; Masayuki Saijo ; Fumihiro Taguchi ; Shigeru Morikawa ; Tetsutaro SataSource :
- The American Journal of Pathology [ 0002-9440 ] ; 2008.
Abstract
Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-α). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-γ, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-α antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-γ injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.
Url:
DOI: 10.2353/ajpath.2008.071060
PubMed: 18467696
PubMed Central: 2408422
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice</title><author><name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Iwata, Naoko" sort="Iwata, Naoko" uniqKey="Iwata N" first="Naoko" last="Iwata">Naoko Iwata</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Fukushi, Shuetsu" sort="Fukushi, Shuetsu" uniqKey="Fukushi S" first="Shuetsu" last="Fukushi">Shuetsu Fukushi</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Harashima, Ayako" sort="Harashima, Ayako" uniqKey="Harashima A" first="Ayako" last="Harashima">Ayako Harashima</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Sato, Yuko" sort="Sato, Yuko" uniqKey="Sato Y" first="Yuko" last="Sato">Yuko Sato</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Saijo, Masayuki" sort="Saijo, Masayuki" uniqKey="Saijo M" first="Masayuki" last="Saijo">Masayuki Saijo</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Morikawa, Shigeru" sort="Morikawa, Shigeru" uniqKey="Morikawa S" first="Shigeru" last="Morikawa">Shigeru Morikawa</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Sata, Tetsutaro" sort="Sata, Tetsutaro" uniqKey="Sata T" first="Tetsutaro" last="Sata">Tetsutaro Sata</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18467696</idno><idno type="pmc">2408422</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408422</idno><idno type="RBID">PMC:2408422</idno><idno type="doi">10.2353/ajpath.2008.071060</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000255</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000255</idno><idno type="wicri:Area/Pmc/Curation">000255</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000255</idno><idno 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id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Fukushi, Shuetsu" sort="Fukushi, Shuetsu" uniqKey="Fukushi S" first="Shuetsu" last="Fukushi">Shuetsu Fukushi</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Harashima, Ayako" sort="Harashima, Ayako" uniqKey="Harashima A" first="Ayako" last="Harashima">Ayako Harashima</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Sato, Yuko" sort="Sato, Yuko" uniqKey="Sato Y" first="Yuko" last="Sato">Yuko Sato</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Saijo, Masayuki" sort="Saijo, Masayuki" uniqKey="Saijo M" first="Masayuki" last="Saijo">Masayuki Saijo</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Morikawa, Shigeru" sort="Morikawa, Shigeru" uniqKey="Morikawa S" first="Shigeru" last="Morikawa">Shigeru Morikawa</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author><author><name sortKey="Sata, Tetsutaro" sort="Sata, Tetsutaro" uniqKey="Sata T" first="Tetsutaro" last="Sata">Tetsutaro Sata</name><affiliation><nlm:aff id="N0x2f95de0N0x3d81b90"></nlm:aff></affiliation></author></analytic><series><title level="j">The American Journal of Pathology</title><idno type="ISSN">0002-9440</idno><idno type="eISSN">1525-2191</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-α). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-γ, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-α antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-γ injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Pathol</journal-id><journal-title>The American Journal of Pathology</journal-title><issn pub-type="ppub">0002-9440</issn><issn pub-type="epub">1525-2191</issn><publisher><publisher-name>American Society for Investigative Pathology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18467696</article-id><article-id pub-id-type="pmc">2408422</article-id><article-id pub-id-type="doi">10.2353/ajpath.2008.071060</article-id><article-categories><subj-group subj-group-type="heading"><subject>Regular Articles</subject><subj-group><subject>Immunopathology and Infectious Diseases</subject></subj-group></subj-group></article-categories><title-group><article-title>Mouse-Passaged Severe Acute Respiratory Syndrome-Associated Coronavirus Leads to Lethal Pulmonary Edema and Diffuse Alveolar Damage in Adult but Not Young Mice</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nagata</surname><given-names>Noriyo</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><contrib contrib-type="author"><name><surname>Iwata</surname><given-names>Naoko</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><contrib contrib-type="author"><name><surname>Hasegawa</surname><given-names>Hideki</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><contrib contrib-type="author"><name><surname>Fukushi</surname><given-names>Shuetsu</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">†</xref></contrib><contrib contrib-type="author"><name><surname>Harashima</surname><given-names>Ayako</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><contrib contrib-type="author"><name><surname>Sato</surname><given-names>Yuko</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><contrib contrib-type="author"><name><surname>Saijo</surname><given-names>Masayuki</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">†</xref></contrib><contrib contrib-type="author"><name><surname>Taguchi</surname><given-names>Fumihiro</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">‡</xref></contrib><contrib contrib-type="author"><name><surname>Morikawa</surname><given-names>Shigeru</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">†</xref></contrib><contrib contrib-type="author"><name><surname>Sata</surname><given-names>Tetsutaro</given-names></name><xref ref-type="aff" rid="N0x2f95de0N0x3d81b90">*</xref></contrib><aff id="N0x2f95de0N0x3d81b90">From the Departments of Pathology,<label>*</label> Virology I,<label>†</label> and Virology III,<label>‡</label> National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan</aff></contrib-group><pub-date pub-type="ppub"><month>6</month><year>2008</year></pub-date><volume>172</volume><issue>6</issue><fpage>1625</fpage><lpage>1637</lpage><history><date date-type="accepted"><day>22</day><month>2</month><year>2008</year></date></history><permissions><copyright-statement>Copyright © American Society for Investigative Pathology</copyright-statement><copyright-year>2008</copyright-year></permissions><self-uri xlink:title="pdf" xlink:href="zjh00608001625.pdf"></self-uri><abstract><p>Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-α). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-γ, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-α antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-γ injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.</p></abstract></article-meta></front><floats-wrap><fig position="float" id="F1-7631"><label>Figure 1</label><caption><p>Comparison of the replication and pathogenicity of F-musX-VeroE6 and the original Frankfurt 1 isolate in young (4 weeks old) (<bold>A–E</bold>) and adult (6 months old) (<bold>F</bold>) female BALB/c mice. <bold>A:</bold> Virus titers in nasal wash fluids, homogenates of maxilla (including the nasal cavity), lung wash fluid, and lung homogenates of young mice on days 3, 5, and 7 after inoculation (<italic>n</italic> = 3 per group). The detection limit was 10<sup>1.5</sup> TCID<sub>50</sub>/g of tissue. <bold>Asterisks</bold> indicate statistically significant differences between F-musX-VeroE6 and the Frankfurt isolate (<italic>P</italic> < 0.05). <bold>B–E:</bold> Histopathological features of the lungs of young mice on day 3 after inoculation. <bold>B:</bold> After infection with the Frankfurt 1 isolate, inflammatory infiltrates in the lung were not detected. Moreover, very few alveolar pneumocytes and alveolar duct and alveolus epithelial cells were SARS-CoV antigen-positive (<bold>C</bold>, <bold>arrowheads</bold>). In contrast, extensive cellular infiltration (<bold>D</bold>) and many virus antigen-positive cells (<bold>E</bold>) were seen in the alveolar area after F-musX-VeroE6 infection. <bold>F:</bold> Clinical illness in individual 6-month-old adult BALB/c mice after Frankfurt isolate or F-musX-VeroE6 infection (<italic>n</italic> = 10 per group). Shown are the changes in body weight (expressed as percentages of the body weight on day 0). The mean initial body weight of the two mouse groups (on day 0) were 24.72 ± 1.04 g and 25.44 ± 1.55 g, respectively. Significant differences in body weight change were detected on days 2 to 8 after inoculation. For example, the average body weight F-musX-VeroE6-infected adult mice on day 5 after inoculation was 83.4 ± 9.88% of the mean day 0 body weight. This was significantly lower than the average body weight change of Frankfurt 1 isolate-infected adult mice on day 5 after inoculation (102.4 ± 2.99%). Three F-musX-VeroE6-infected adult mice died (crosses) of severe pulmonary edema on days 3, 6, and 10 after inoculation.</p></caption><graphic xlink:href="zjh0060876310001"></graphic></fig><fig position="float" id="F2-7631"><label>Figure 2</label><caption><p>The pathophysiology induced by mouse-passaged SARS-CoV differs between young and adult mice. F-musX-VeroE6-infected young and adult mice were examined at the same time points after inoculation. <bold>Asterisks</bold> indicate statistically significant differences between young and adult mice (<italic>P</italic> < 0.05). <bold>A:</bold> Mean change in body weight (expressed as a percentage of the body weight on day 0) (<italic>n</italic> = 6 per group). Three (50%) of the adult mice became moribund and died (crosses) by day 5 after inoculation. <bold>B:</bold> To assess the lungs for pulmonary edema, the lungs were weighed after mice were sacrificed on days 1 to 5 after inoculation by exsanguination under anesthesia (<italic>n</italic> = 3 per group). <bold>C:</bold> Lungs from virus- and mock-infected young and adult mice obtained at the indicated time points after inoculation. <bold>Arrowheads</bold> indicate focal congestion. On day 5 after inoculation, a moribund adult mouse had dark red congested lungs. <bold>D</bold> and <bold>E:</bold> Virus titers in the nasal (pale green bar) and lung (yellow bar) wash fluids and homogenates of the maxilla (including nasal cavity, green bar) and lung (orange bar) on days 1 to 5 after inoculation (<italic>n</italic> = 3 per group). The detection limit was 10<sup>1.5</sup> TCID<sub>50</sub>/g of tissue.</p></caption><graphic xlink:href="zjh0060876310002"></graphic></fig><fig position="float" id="F3-7631"><label>Figure 3</label><caption><p>Histopathological findings in the lungs of young (<bold>A–D</bold>) and adult (<bold>E–H</bold>) mice on days 1 (<bold>A</bold>, <bold>E</bold>), 2 (<bold>B</bold>, <bold>F</bold>), and 3 (<bold>C</bold>, <bold>D</bold>, <bold>G</bold>, <bold>H</bold>) after inoculation. Br, bronchi; Al, alveoli; BV, blood vessel; H, hyaline membrane. The results in each panel are representative of at least three mice for each panel. Immunohistochemical staining with anti-SARS-CoV-specific antibody revealed virus antigen-positive cells in pulmonary epithelial cells of the bronchi and alveolar area, and type II pneumocytes (<bold>inset</bold>) in both young and adult mice on day 1 after inoculation (<bold>A</bold>, <bold>E</bold>). On day 2 after inoculation, atrophic cells in the alveolar area of young mice were positive for virus antigen (<bold>B</bold>, <bold>inset</bold>). In adult mice at the same time point activated alveolar macrophages presented in the alveolar space were also positive for virus antigen (<bold>F</bold>, <bold>inset</bold>). On day 3 after inoculation, the young mice showed slight inflammatory mononuclear cell infiltration in the alveolar area (<bold>C</bold>, <bold>inset</bold>; and <bold>D</bold>) but the adult mice exhibited massive pulmonary edema and inflammatory polynuclear leukocyte infiltration around blood vessels (<bold>G</bold>, <bold>inset</bold>). <bold>H:</bold> They also showed hyaline membrane formation in the alveolar duct.</p></caption><graphic xlink:href="zjh0060876310003"></graphic></fig><fig position="float" id="F4-7631"><label>Figure 4</label><caption><p>White blood cell (WBC) counts in young and adult mice throughout time after inoculation. Shown are total WBC, neutrophil, monocyte, lymphocyte, CD4-positive cell, CD8β-positive cell, and NK cell counts in the peripheral blood of young and adult mice after intranasal inoculation with mouse-passaged SARS-CoV (<italic>n</italic> = 3). *<italic>P</italic> < 0.05 indicate statistically significant differences between young and adult mice at the same time point. <sup>#</sup><italic>P</italic> < 0.05 and <sup>+</sup><italic>P</italic> < 0.05 indicate statistically significant differences within groups relative to day 0 in young or adult mice, respectively.</p></caption><graphic xlink:href="zjh0060876310004"></graphic></fig><fig position="float" id="F5-7631"><label>Figure 5</label><caption><p>Chemokine protein levels in the lungs of young (white bar) and adult (black bar) mice throughout time after inoculation (<italic>n</italic> = 3 per group). <bold>Asterisks</bold> indicate statistically significant higher or lower chemokine levels in adult mice (<italic>P</italic> < 0.05) compared to young BALB/c mice. Adult mice showed earlier induction of MCP-1, MIP-1, and IP-10 in the lungs than young mice but these three chemokines and MIG and VEGF were at significantly higher levels in the lungs of young mice on day 2 after inoculation.</p></caption><graphic xlink:href="zjh0060876310005"></graphic></fig><fig position="float" id="F6-7631"><label>Figure 6</label><caption><p>Cytokine protein levels in lungs and plasma throughout time after inoculation (<italic>n</italic> = 3 per group; <sup>+</sup><italic>n</italic> = 6; <sup>#</sup><italic>n</italic> = 4). <bold>Asterisks</bold> indicate statistically significant higher or lower cytokine levels in adult mice (<italic>P</italic> < 0.05) compared to in young mice. The adult mice had significantly higher levels of IL-1α, IL-1β, IL-6, TNF-α, and IL-4 whereas the young mice had significantly higher levels of IL-2, IL-12, IFN-γ, IL-10, and IL-13.</p></caption><graphic xlink:href="zjh0060876310006"></graphic></fig><fig position="float" id="F7-7631"><label>Figure 7</label><caption><p>Effect of anti-TNF-α antibody or IFN-γ injections of infected adult mice on body weight change throughout time after inoculation. Adult mice were infected with F-musX-VeroE6 by intranasal inoculation and injected intravenously with anti-TNF-α antibody or intraperitoneally with IFN-γ 3 hours after inoculation. Mean percentages of body weight change of the animals were determined for 10 days after inoculation. <bold>Crosses</bold> indicate dead mice. <bold>Asterisks</bold> indicate statistically significant differences in weight loss (<italic>P</italic> < 0.05) compared to control animals. The results shown in each panel are representative of at least two independent experiments for each panel (<italic>n</italic> = 5 to 8 per group). <bold>A:</bold> Effect of anti-TNF-α antibody (<italic>n</italic> = 8 per group). The control group was injected intravenously with rat IgG. <bold>B:</bold> Effect of IFN-γ (<italic>n</italic> = 8 per group). The control group was injected with PBS intraperitoneally. <bold>C:</bold> Virus titers in the nasal (pale green bar) and lung (yellow bar) wash fluids and homogenates of the maxilla (including nasal cavity, green bar) and lung (orange bar) on days 3 after inoculation of PBS- and IFN-γ-treated adult mice (<italic>n</italic> = 3 per group). The detection limit was 10<sup>1.5</sup> TCID<sub>50</sub>/g of tissue. <bold>D</bold> and <bold>E:</bold> Lung histopathology in IFN-γ- and PBS-treated adult mice, respectively. BV, blood vessel; Br, bronchi. Mononuclear cell infiltration was seen in the alveolar area and around blood vessels in the lungs of the IFN-γ-injected mice (<bold>D</bold>, <bold>inset</bold>). In contrast, the lungs of PBS-injected mice exhibited polynuclear leukocyte infiltration around edematous blood vessels (<bold>E</bold>, <bold>inset</bold>).</p></caption><graphic xlink:href="zjh0060876310007"></graphic></fig><fig position="float" id="F8-7631"><label>Figure 8</label><caption><p><bold>A–G:</bold> IFN-γ treatment protects mice from infection-induced blood vessel hyperpermeability in the lung. Virus-infected adult mice (<italic>n</italic> = 3) were injected intraperitoneally with IFN-γ or PBS and the effect of these treatments on lung blood vessel permeability was determined by using Evans blue dye extravasation. <bold>A:</bold> Blue discoloration of the lung tissue of IFN-γ- and PBS-treated mice 3 days after inoculation. The black lines indicate the areas examined in more detail in <bold>B–G</bold>. <bold>B–G:</bold> The deposition of Evans blue dye in lung tissue (pink) was examined in frozen sections of the formalin-fixed tissue by using a fluorescence microscope. Scale bars: 200 μm (<bold>B–D</bold>); 100 μm (<bold>E–G</bold>).</p></caption><graphic xlink:href="zjh0060876310008"></graphic></fig><table-wrap position="float" id="T1-7631"><label>Table 1</label><caption><p>Virus Isolation from Different Tissues of F-musX-VeroE6-Infected BALB/c Mice at Various Time Points after Inoculation (<italic>n</italic> = 3 per Time Point)</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="bottom">Days after inoculation</th><th colspan="5" rowspan="1" align="center" valign="bottom">Young mice (4-week-old BALB/c)
<hr></hr></th><th colspan="5" rowspan="1" align="center" valign="bottom">Adult mice (6-month-old BALB/c)
<hr></hr></th></tr><tr><th colspan="1" rowspan="1" align="center" valign="bottom">Lung</th><th colspan="1" rowspan="1" align="center" valign="bottom">Cervical L/N</th><th colspan="1" rowspan="1" align="center" valign="bottom">Spleen</th><th colspan="1" rowspan="1" align="center" valign="bottom">Liver</th><th colspan="1" rowspan="1" align="center" valign="bottom">Kidney</th><th colspan="1" rowspan="1" align="center" valign="bottom">Lung</th><th colspan="1" rowspan="1" align="center" valign="bottom">Cervical L/N</th><th colspan="1" rowspan="1" align="center" valign="bottom">Spleen</th><th colspan="1" rowspan="1" align="center" valign="bottom">Liver</th><th colspan="1" rowspan="1" align="center" valign="bottom">Kidney</th></tr></thead><tbody><tr><td>0 days</td><td>0<xref rid="TFN1-1-7631" ref-type="other">*</xref></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>1 day</td><td>3</td><td>3</td><td>3</td><td>1</td><td>0</td><td>3</td><td>3</td><td>3</td><td>3</td><td>0</td></tr><tr><td>2 days</td><td>3</td><td>3</td><td>2</td><td>2</td><td>0</td><td>3</td><td>3</td><td>2</td><td>2</td><td>1</td></tr><tr><td>3 days</td><td>3</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3</td><td>2</td><td>1</td><td>1</td><td>1</td></tr><tr><td>4 days</td><td>3</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3</td><td>2</td><td>0</td><td>0</td><td>0</td></tr><tr><td>5 days</td><td>3</td><td>0</td><td>0</td><td>0</td><td>0</td><td>3</td><td>0</td><td>1</td><td>0</td><td>0</td></tr></tbody></table><table-wrap-foot><fn id="TFN1-1-7631"><label>*</label><p>Number of virus isolation-positive animals. </p></fn><fn><p>L/N, lymph node. </p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc><affiliations><list></list><tree><noCountry><name sortKey="Fukushi, Shuetsu" sort="Fukushi, Shuetsu" uniqKey="Fukushi S" first="Shuetsu" last="Fukushi">Shuetsu Fukushi</name><name sortKey="Harashima, Ayako" sort="Harashima, Ayako" uniqKey="Harashima A" first="Ayako" last="Harashima">Ayako Harashima</name><name sortKey="Hasegawa, Hideki" sort="Hasegawa, Hideki" uniqKey="Hasegawa H" first="Hideki" last="Hasegawa">Hideki Hasegawa</name><name sortKey="Iwata, Naoko" sort="Iwata, Naoko" uniqKey="Iwata N" first="Naoko" last="Iwata">Naoko Iwata</name><name sortKey="Morikawa, Shigeru" sort="Morikawa, Shigeru" uniqKey="Morikawa S" first="Shigeru" last="Morikawa">Shigeru Morikawa</name><name sortKey="Nagata, Noriyo" sort="Nagata, Noriyo" uniqKey="Nagata N" first="Noriyo" last="Nagata">Noriyo Nagata</name><name sortKey="Saijo, Masayuki" sort="Saijo, Masayuki" uniqKey="Saijo M" first="Masayuki" last="Saijo">Masayuki Saijo</name><name sortKey="Sata, Tetsutaro" sort="Sata, Tetsutaro" uniqKey="Sata T" first="Tetsutaro" last="Sata">Tetsutaro Sata</name><name sortKey="Sato, Yuko" sort="Sato, Yuko" uniqKey="Sato Y" first="Yuko" last="Sato">Yuko Sato</name><name sortKey="Taguchi, Fumihiro" sort="Taguchi, Fumihiro" uniqKey="Taguchi F" first="Fumihiro" last="Taguchi">Fumihiro Taguchi</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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