Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 308, Issue 11, Pages L1136-L1144Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00078.2015
Keywords
acute lung injury; cystic fibrosis transmembrane conductance regulator; interleukin-6; influenza; transforming growth factor-beta
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Funding
- Ohio State University Howard Hughes Medical Institute Med-to-Grad Training Program
- C. Glenn Barber Fund
- Careers in Immunology Fellowship from the American Association of Immunologists
- Ohio State University Systems and Integrative Biology Training Program Grant from the National Institute of General Medical Sciences at the National Institutes of Health [T32-GM068412]
- Cystic Fibrosis Foundation Research Grant
- Ohio State University Public Health Preparedness in Infectious Diseases Program
- National Heart Lung and Blood Institute at the National Institutes of Health [R01-HL102469]
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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-beta production by HET but not WT mice at 2 d.p.i. TGF-beta 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-gamma 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-beta-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice.
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