tetano
Editor, Senior Moderator
Am J Physiol Lung Cell Mol Physiol. 2015 Apr 3:ajplung.00078.2015. doi: 10.1152/ajplung.00078.2015. [Epub ahead of print]
[h=1]TGF-β-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice.[/h] Woods PS[SUP]1[/SUP], Tazi MF[SUP]1[/SUP], Chesarino NM[SUP]1[/SUP], Amer AO[SUP]1[/SUP], Davis IC[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] As the 8[SUP]th[/SUP] 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, pathophysiologic 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 post-infection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the current 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 post-infection 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/KC 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.
Copyright ? 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology.
[h=4]KEYWORDS:[/h] Acute lung injury; CFTR; IL-6; Influenza; Transforming growth factor-beta
PMID: 25840995 [PubMed - as supplied by publisher]
[h=1]TGF-β-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice.[/h] Woods PS[SUP]1[/SUP], Tazi MF[SUP]1[/SUP], Chesarino NM[SUP]1[/SUP], Amer AO[SUP]1[/SUP], Davis IC[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] As the 8[SUP]th[/SUP] 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, pathophysiologic 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 post-infection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the current 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 post-infection 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/KC 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.
Copyright ? 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology.
[h=4]KEYWORDS:[/h] Acute lung injury; CFTR; IL-6; Influenza; Transforming growth factor-beta
PMID: 25840995 [PubMed - as supplied by publisher]