tetano
Editor, Senior Moderator
JCI Insight. 2018 Dec 20;3(24). pii: 99022. doi: 10.1172/jci.insight.99022. [Epub ahead of print]
[h=1]Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection.[/h] Rojas-Quintero J[SUP]1[/SUP], Wang X[SUP]1[/SUP], Tipper J[SUP]2[/SUP], Burkett PR[SUP]1[/SUP], Zu?iga J[SUP]3[/SUP], Ashtekar AR[SUP]2[/SUP], Polverino F[SUP]1,[/SUP][SUP]4[/SUP], Rout A[SUP]1[/SUP], Yambayev I[SUP]1[/SUP], Hern?ndez C[SUP]3,[/SUP][SUP]5[/SUP], Jimenez L[SUP]3[/SUP], Ram?rez G[SUP]3[/SUP], Harrod KS[SUP]2[/SUP], Owen CA[SUP]1,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Matrix metalloproteinase-9 (MMP-9) cleaves various proteins to regulate inflammatory and injury responses. However, MMP-9's activities during influenza A viral (IAV) infections are incompletely understood. Herein, plasma MMP-9 levels were increased in patients with pandemic H1N1 and seasonal IAV infections. MMP-9 lung levels were increased and localized to airway epithelial cells and leukocytes in H1N1-infected WT murine lungs. H1N1-infected Mmp-9-/- mice had lower mortality rates, reduced weight loss, lower lung viral titers, and reduced lung injury, along with lower E-cadherin shedding in bronchoalveolar lavage fluid (BALF) samples than WT mice. H1N1-infected Mmp-9-/- mice had an altered immune response to IAV with lower BALF PMN and macrophage counts, higher Th1-like CD4+ and CD8+ T cell subsets, lower T regulatory cell counts, reduced lung type I interferon levels, and higher lung interferon-γ levels. Mmp-9 bone marrow-chimera studies revealed that Mmp-9 deficiency in lung parenchymal cells protected mice from IAV-induced mortality. H1N1-infected Mmp-9-/- lung epithelial cells had lower viral titers than H1N1-infected WT cells in vitro. Thus, H1N1-infected Mmp-9-/- mice are protected from IAV-induced lung disease due to a more effective adaptive immune response to IAV and reduced epithelial barrier injury due partly to reduced E-cadherin shedding. Thus, we believe that MMP-9 is a novel therapeutic target for IAV infections.
[h=4]KEYWORDS:[/h] Infectious disease; Influenza; Mouse models; Pulmonology
PMID: 30568032 DOI: 10.1172/jci.insight.99022
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[h=1]Matrix metalloproteinase-9 deficiency protects mice from severe influenza A viral infection.[/h] Rojas-Quintero J[SUP]1[/SUP], Wang X[SUP]1[/SUP], Tipper J[SUP]2[/SUP], Burkett PR[SUP]1[/SUP], Zu?iga J[SUP]3[/SUP], Ashtekar AR[SUP]2[/SUP], Polverino F[SUP]1,[/SUP][SUP]4[/SUP], Rout A[SUP]1[/SUP], Yambayev I[SUP]1[/SUP], Hern?ndez C[SUP]3,[/SUP][SUP]5[/SUP], Jimenez L[SUP]3[/SUP], Ram?rez G[SUP]3[/SUP], Harrod KS[SUP]2[/SUP], Owen CA[SUP]1,[/SUP][SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Matrix metalloproteinase-9 (MMP-9) cleaves various proteins to regulate inflammatory and injury responses. However, MMP-9's activities during influenza A viral (IAV) infections are incompletely understood. Herein, plasma MMP-9 levels were increased in patients with pandemic H1N1 and seasonal IAV infections. MMP-9 lung levels were increased and localized to airway epithelial cells and leukocytes in H1N1-infected WT murine lungs. H1N1-infected Mmp-9-/- mice had lower mortality rates, reduced weight loss, lower lung viral titers, and reduced lung injury, along with lower E-cadherin shedding in bronchoalveolar lavage fluid (BALF) samples than WT mice. H1N1-infected Mmp-9-/- mice had an altered immune response to IAV with lower BALF PMN and macrophage counts, higher Th1-like CD4+ and CD8+ T cell subsets, lower T regulatory cell counts, reduced lung type I interferon levels, and higher lung interferon-γ levels. Mmp-9 bone marrow-chimera studies revealed that Mmp-9 deficiency in lung parenchymal cells protected mice from IAV-induced mortality. H1N1-infected Mmp-9-/- lung epithelial cells had lower viral titers than H1N1-infected WT cells in vitro. Thus, H1N1-infected Mmp-9-/- mice are protected from IAV-induced lung disease due to a more effective adaptive immune response to IAV and reduced epithelial barrier injury due partly to reduced E-cadherin shedding. Thus, we believe that MMP-9 is a novel therapeutic target for IAV infections.
[h=4]KEYWORDS:[/h] Infectious disease; Influenza; Mouse models; Pulmonology
PMID: 30568032 DOI: 10.1172/jci.insight.99022
Free full text