Limits...
Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment

View Article: PubMed Central - PubMed

ABSTRACT

Influenza A viruses are important human and animal pathogens. Seasonal influenza viruses cause infections every year, and occasionally zoonotic viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. Three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus were reported in 2013, and there have been several cases reported across South East Asia, and recently in North America. Most patients experience severe respiratory illness, with mortality rates approaching 40%. No vaccine is currently available and the use of antivirals is complicated due to the emergence of drug resistant strains. Thus, there is a need to identify new drugs for therapeutic intervention and disease control. In humans, following H7N9 infection, there is excessive expression of pro-inflammatory factors CCL2, IL-6, IL-8, IFNα, interferon-γ, IP-10, MIG and macrophage inflammatory protein-1β, which has been shown to contribute to fatal disease outcomes in mouse models of infection. In the current study, the potent inhibitor of CCL2 synthesis, Bindarit, was examined as a countermeasure for H7N9-induced inflammation in a mouse model. Bindarit treatment of mice did not have any substantial therapeutic efficacy in H7N9 infection. Consequently, the results suggest that Bindarit may be ill-advised in the treatment of influenza H7N9 infection.

No MeSH data available.


Related in: MedlinePlus

Effect of Bindarit on histopathological changes following avian IAV H7N9 infection. Mice were infected i.n. with a lethal dose (10 × LD50) of H7N9 or PBS. Mice were then treated with either Bindarit or vehicle starting at day 1 pi. At day 4 pi, mice were killed and lungs collected for histopathological analysis. Mock-infected methylcellulose (a) and Bindarit-treated (b). Viable epithelial cells line the bronchioles and there is no exudate within the lumen. No peribronchiolar or perivascular infiltrations are present and the parenchyma has no changes. H7N9-infected methylcellulose (c) and Bindarit-treated (d). There is diffuse necrosis and loss of the bronchiolar epithelium with luminal necrotic cellular debris lining the denuded wall. A mild to moderate peribronchiolar and perivascular infiltration of mostly lymphocytes is also present. Parenchymal changes are mild to moderate with mild thickening of the alveolar septa and a few inflammatory cells in alveoli. Data are from three mice per group. B, bronchiole; P, parenchyma; V, vessel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382437&req=5

fig3: Effect of Bindarit on histopathological changes following avian IAV H7N9 infection. Mice were infected i.n. with a lethal dose (10 × LD50) of H7N9 or PBS. Mice were then treated with either Bindarit or vehicle starting at day 1 pi. At day 4 pi, mice were killed and lungs collected for histopathological analysis. Mock-infected methylcellulose (a) and Bindarit-treated (b). Viable epithelial cells line the bronchioles and there is no exudate within the lumen. No peribronchiolar or perivascular infiltrations are present and the parenchyma has no changes. H7N9-infected methylcellulose (c) and Bindarit-treated (d). There is diffuse necrosis and loss of the bronchiolar epithelium with luminal necrotic cellular debris lining the denuded wall. A mild to moderate peribronchiolar and perivascular infiltration of mostly lymphocytes is also present. Parenchymal changes are mild to moderate with mild thickening of the alveolar septa and a few inflammatory cells in alveoli. Data are from three mice per group. B, bronchiole; P, parenchyma; V, vessel.

Mentions: The effect of Bindarit on lung inflammation and pathology was investigated in mice infected with H7N9. Mice were i.n. infected with a lethal dose of H7N9 (105 PFU) and orally treated with Bindarit (70 mg kg−1) twice daily starting at day 1 pi. Mice were killed at day 4 pi and lungs were collected for histopathology. Lungs in both groups, mock- and Bindarit-treated, showed moderate to severe necrotic bronchitis and bronchiolitis. The peribronchiolar and perivascular infiltration was mild to moderate for both groups and animals showed mild to severe alveolitis (Figures 3c and d). Two mock-treated mice infected with H7N9 developed hemorrhage, a feature that was not observed in Bindarit-treated animals. Taken together, there were no substantial changes in histopathology when mice were orally treated with Bindarit (70 mg kg−1). All mice showed a lung score of 3 (Table 1).


Targeting the pro-inflammatory factor CCL2 (MCP-1) with Bindarit for influenza A (H7N9) treatment
Effect of Bindarit on histopathological changes following avian IAV H7N9 infection. Mice were infected i.n. with a lethal dose (10 × LD50) of H7N9 or PBS. Mice were then treated with either Bindarit or vehicle starting at day 1 pi. At day 4 pi, mice were killed and lungs collected for histopathological analysis. Mock-infected methylcellulose (a) and Bindarit-treated (b). Viable epithelial cells line the bronchioles and there is no exudate within the lumen. No peribronchiolar or perivascular infiltrations are present and the parenchyma has no changes. H7N9-infected methylcellulose (c) and Bindarit-treated (d). There is diffuse necrosis and loss of the bronchiolar epithelium with luminal necrotic cellular debris lining the denuded wall. A mild to moderate peribronchiolar and perivascular infiltration of mostly lymphocytes is also present. Parenchymal changes are mild to moderate with mild thickening of the alveolar septa and a few inflammatory cells in alveoli. Data are from three mice per group. B, bronchiole; P, parenchyma; V, vessel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382437&req=5

fig3: Effect of Bindarit on histopathological changes following avian IAV H7N9 infection. Mice were infected i.n. with a lethal dose (10 × LD50) of H7N9 or PBS. Mice were then treated with either Bindarit or vehicle starting at day 1 pi. At day 4 pi, mice were killed and lungs collected for histopathological analysis. Mock-infected methylcellulose (a) and Bindarit-treated (b). Viable epithelial cells line the bronchioles and there is no exudate within the lumen. No peribronchiolar or perivascular infiltrations are present and the parenchyma has no changes. H7N9-infected methylcellulose (c) and Bindarit-treated (d). There is diffuse necrosis and loss of the bronchiolar epithelium with luminal necrotic cellular debris lining the denuded wall. A mild to moderate peribronchiolar and perivascular infiltration of mostly lymphocytes is also present. Parenchymal changes are mild to moderate with mild thickening of the alveolar septa and a few inflammatory cells in alveoli. Data are from three mice per group. B, bronchiole; P, parenchyma; V, vessel.
Mentions: The effect of Bindarit on lung inflammation and pathology was investigated in mice infected with H7N9. Mice were i.n. infected with a lethal dose of H7N9 (105 PFU) and orally treated with Bindarit (70 mg kg−1) twice daily starting at day 1 pi. Mice were killed at day 4 pi and lungs were collected for histopathology. Lungs in both groups, mock- and Bindarit-treated, showed moderate to severe necrotic bronchitis and bronchiolitis. The peribronchiolar and perivascular infiltration was mild to moderate for both groups and animals showed mild to severe alveolitis (Figures 3c and d). Two mock-treated mice infected with H7N9 developed hemorrhage, a feature that was not observed in Bindarit-treated animals. Taken together, there were no substantial changes in histopathology when mice were orally treated with Bindarit (70 mg kg−1). All mice showed a lung score of 3 (Table 1).

View Article: PubMed Central - PubMed

ABSTRACT

Influenza A viruses are important human and animal pathogens. Seasonal influenza viruses cause infections every year, and occasionally zoonotic viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. Three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus were reported in 2013, and there have been several cases reported across South East Asia, and recently in North America. Most patients experience severe respiratory illness, with mortality rates approaching 40%. No vaccine is currently available and the use of antivirals is complicated due to the emergence of drug resistant strains. Thus, there is a need to identify new drugs for therapeutic intervention and disease control. In humans, following H7N9 infection, there is excessive expression of pro-inflammatory factors CCL2, IL-6, IL-8, IFNα, interferon-γ, IP-10, MIG and macrophage inflammatory protein-1β, which has been shown to contribute to fatal disease outcomes in mouse models of infection. In the current study, the potent inhibitor of CCL2 synthesis, Bindarit, was examined as a countermeasure for H7N9-induced inflammation in a mouse model. Bindarit treatment of mice did not have any substantial therapeutic efficacy in H7N9 infection. Consequently, the results suggest that Bindarit may be ill-advised in the treatment of influenza H7N9 infection.

No MeSH data available.


Related in: MedlinePlus