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Results: 7

1.
Figure 7

Figure 7. Proposed model for PAR1-mediated influenza virus pathogenesis.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

During IAV infection, PAR1 is activated and increases conversion of PLG into plasmin. On the one hand, plasmin cleaves and activates the viral HA, promoting IAV replication, which contributes to inflammation. On the other hand, plasmin directly promotes inflammation, and PAR1 promotes inflammation via mechanisms that are independent of PLG and virus. These likely interact with other host responses to viral infection to exacerbate inflammation and injury.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
2.
Figure 6

Figure 6. PAR1 antagonist protects mice from lethal infection with H5N1 or H1N1v.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

Mice were inoculated intranasally with (A) 5,000 PFU H5N1 (n = 10 per group) or (B) 500 PFU H1N1v (n = 10–11 per group) and treated or not with 50 μM SCH79797. Results are expressed as percent survival or weight loss from 2 experiments. *P < 0.05, treated vs. control, Kaplan-Meier test.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
3.
Figure 4

Figure 4. PAR1 antagonist protects mice against infection with H1N1 and H3N2.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

(A) Treatment of NIH3T3 cells with SCH79797 blocked ERK activation by 10 μM PAR1-AP. (B) SCH79797 treatment prevented PAR1-AP–induced mouse mortality in a dose-dependent manner. (C) IAV-induced pathogenesis in infected mice treated or not with SCH79797. Mice were inoculated with 500 PFU (n = 17–19 per group) or 5,000 PFU (n = 14 per group) H1N1 and treated or not with 50 μM SCH79797 on days 0–2 after infection. (D) SCH79797 treatment on days 2–4 after infection with 5,000 PFU H1N1 (n = 12 per group) or 100 PFU H3N2 (n = 7 per group). (E) SCH79797 treatment on days 3–5 after infection with 5,000 PFU H1N1 (n = 7 per group) or 100 PFU H3N2 (n = 7 per group). *P < 0.05, treated vs. control, Kaplan-Meier test.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
4.
Figure 5

Figure 5. PAR1 antagonist inhibits lung inflammation and virus replication.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

(A) Cytokines in the BAL of infected mice treated or not with SCH79797 were measured by ELISA 24, 48, and 72 hours after inoculation. Data are average ± SD from 7–11 individual animals per group, representative of 3 experiments. (B) Relative PMN frequency in BAL from infected mice treated or not with SCH79797. PMN percentage was determined by May-Grünwald–Giemsa staining 24, 48, and 72 hours after inoculation. Data are average ± SD from 3–5 individual mice per group. Noninfected mice were used as control (n = 3–5 per group). Results are representative of 2 individual experiments. (C) Virus titers in lungs of infected mice at the indicated times after infection with 500 PFU H1N1 and treatment with SCH79797. Data are average ± SD from 3–5 individual animals per group. *P < 0.05, treated vs. control, Mann-Whitney test.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
5.
Figure 2

Figure 2. PAR1-AP increases inflammation and virus replication during 50 PFU H1N1 infection in mice.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

(A) Cytokines in the BAL of infected mice treated or not with PAR1-AP were measured by ELISA 24, 48, and 72 hours after inoculation. Data are mean ± SD from 5–11 individual animals per group from 3 experiments. (B) Relative PMN numbers in BAL from infected mice treated or not with PAR1-AP. PMN percentage was determined by May-Grünwald–Giemsa staining 24, 48, or 72 hours after inoculation. Results are mean ± SD from 4–5 individual mice per group from 2 individual experiments. Noninfected mice were used as control (n = 2–4 per group). (C) H1N1 virus titers in the lungs at the indicated times after infection of mice treated or not with 50 μM PAR1-AP. Data are average ± SD from 3–5 individual animals per group. *P < 0.05, treated vs. untreated, Mann-Whitney test.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
6.
Figure 1

Figure 1. Effect of PAR1 activation and PAR1 deficiency on IAV pathogenicity.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

(A) Time course of IAV-induced pathogenesis and death in mice in response to PAR1 stimulation. Mice were inoculated intranasally with H1N1 (50 PFU, n = 22 per group; 500 PFU, n = 18 per group) and treated with either vehicle or 50 μM PAR1-AP. (B) Time course of uninfected mice treated or not with 50 μM PAR1-AP (n = 13 per group). (C) Mice were infected with 50 PFU H1N1 and treated with control peptide or vehicle (n = 10 per group). Results are average percent survival or weight loss from 3 independent experiments. (D) Survival and weight loss of Par1–/– mice and WT littermates after infection with 100 PFU H1N1 (n = 12 per group). Results are average percent survival or weight loss from 2 experiments. P < 0.05, PAR1-AP vs. untreated or Par1–/– vs. WT, Kaplan-Meier test.

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.
7.
Figure 3

Figure 3. Effect of PLG and PLG deficiency on IAV production and PAR1-AP effects.. From: PAR1 contributes to influenza A virus pathogenicity in mice.

(A) ERK phosphorylation after stimulation of A549 cells with the indicated PAR1-AP concentrations. Anti–phospho-Erk and anti-Erk antibodies were used. (B) Infectious virus titers in the supernatant of infected cells after stimulation with 40 μM PAR1-AP or control peptide in the presence or absence of PLG. (C) Noninfected (NI) or infected (INF) cells were stimulated with 40 μM PAR1-AP or control peptide in the presence or absence of PLG. After cell lysis, proteins were analyzed by Western blot for HA cleavage. (D) Time course of IAV-induced pathogenesis in Plg–/– and WT littermates after treatment or not with PAR1-AP (n = 9–10 mice per group from 2 experiments). (E) Virus titers 48 hours after infection (50 PFU) in lungs of WT or Plg–/– mice stimulated or not with 50 μM PAR1-AP. Data are average ± SD from 5 individual animals per group from 2 experiments. *P < 0.05, treated vs. untreated, Kaplan-Meier test (D), Mann Whitney test (B and E).

Khaled Khoufache, et al. J Clin Invest. 2013 January 2;123(1):206-214.

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