TGF-β-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice
| Autor: | Mia Tazi, Ian C. Davis, Parker S. Woods, Nicholas M. Chesarino, Amal O. Amer |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Pulmonary and Respiratory Medicine
Chemokine Mice 129 Strain animal structures Physiology Acute Lung Injury Biology Lung injury medicine.disease_cause Orthomyxoviridae Infections Transforming Growth Factor beta Physiology (medical) Macrophages Alveolar medicine Influenza A virus Animals Mice Inbred CFTR Interleukin 6 Sequence Deletion Lung medicine.diagnostic_test Interleukin-6 cystic fibrosis transmembrane conductance regulator transforming growth factor-β Cell Biology respiratory system Pulmonary edema medicine.disease Immunity Innate Cystic fibrosis transmembrane conductance regulator respiratory tract diseases 3. Good health Mice Inbred C57BL Bronchoalveolar lavage medicine.anatomical_structure Immunology Call for Papers biology.protein influenza Bronchoalveolar Lavage Fluid |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | As the eighth leading cause of annual mortality in the USA, influenza A viruses are a major public health concern. In 20% of patients, severe influenza progresses to acute lung injury (ALI). However, pathophysiological mechanisms underlying ALI development are poorly defined. We reported that, unlike wild-type (WT) C57BL/6 controls, influenza A virus-infected mice that are heterozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (HETs) did not develop ALI. This effect was associated with higher IL-6 and alveolar macrophages (AMs) at 6 days postinfection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the present study, we found that HET AMs were an important source of IL-6 at 6 d.p.i. Infection also induced TGF-β production by HET but not WT mice at 2 d.p.i. TGF-β neutralization at 2 d.p.i. (TGF-N) significantly reduced BALF IL-6 in HETs at 6 d.p.i. Neither TGF-N nor IL-6 neutralization at 4 d.p.i. (IL-6-N) altered postinfection weight loss or viral replication in either mouse strain. However, both treatments increased influenza A virus-induced hypoxemia, pulmonary edema, and lung dysfunction in HETs to WT levels at 6 d.p.i. TGF-N and IL-6-N did not affect BALF AM and neutrophil numbers but attenuated the CXCL-1/keratinocyte chemokine response in both strains and reduced IFN-γ production in WT mice. Finally, bone marrow transfer experiments showed that HET stromal and myeloid cells are both required for protection from ALI in HETs. These findings indicate that TGF-β-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice. |
| Databáze: | OpenAIRE |
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