AMG487 alleviates influenza A (H1N1) virus-induced pulmonary inflammation through decreasing IFN-γ-producing lymphocytes and IFN-γ concentrations.
Br J Pharmacol
; 181(13): 2053-2069, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38500396
ABSTRACT
BACKGROUND AND PURPOSE:
Severe influenza virus-infected patients have high systemic levels of Th1 cytokines (including IFN-γ). Intrapulmonary IFN-γ increases pulmonary IFN-γ-producing T lymphocytes through the CXCR3 pathway. Virus-infected mice lacking IP-10/CXCR3 demonstrate lower pulmonary neutrophilic inflammation. AMG487, an IP-10/CXCR3 antagonist, ameliorates virus-induced lung injury in vivo through decreasing viral loads. This study examined whether AMG487 could treat H1N1 virus-induced mouse illness through reducing viral loads or decreasing the number of lymphocytes or neutrophils. EXPERIMENTALAPPROACH:
Here, we studied the above-mentioned effects and underlying mechanisms in vivo. KEYRESULTS:
H1N1 virus infection caused bad overall condition and pulmonary inflammation characterized by the infiltration of lymphocytes and neutrophils. From Day-5 to Day-10 post-virus infection, bad overall condition, pulmonary lymphocytes, and IFN-γ concentrations increased, while pulmonary H1N1 viral titres and neutrophils decreased. Both anti-IFN-γ and AMG487 alleviated virus infection-induced bad overall condition and pulmonary lymphocytic inflammation. Pulmonary neutrophilic inflammation was mitigated by AMG487 on Day-5 post-infection, but was not mitigated by AMG487 on Day-10 post-infection. H1N1 virus induced increases of IFN-γ, IP-10, and IFN-γ-producing lymphocytes and activation of the Jak2-Stat1 pathways in mouse lungs, which were inhibited by AMG487. Anti-IFN-γ decreased IFN-γ and IFN-γ-producing lymphocytes on Day-5 post-infection. AMG487 but not anti-IFN-γ decreased viral titres in mouse lung homogenates or BALF. Higher virus load did not increase pulmonary inflammation and IFN-γ concentrations when mice were treated with AMG487. CONCLUSION AND IMPLICATIONS AMG487 may ameliorate H1N1 virus-induced pulmonary inflammation through decreasing IFN-γ-producing lymphocytes rather than reducing viral loads or neutrophils.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
4_TD
Problema de salud:
4_pneumonia
Asunto principal:
Linfocitos
/
Interferón gamma
/
Infecciones por Orthomyxoviridae
/
Subtipo H1N1 del Virus de la Influenza A
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2024
Tipo del documento:
Article
País de afiliación:
China