tetano
Editor, Senior Moderator
Am J Respir Crit Care Med. 2015 Mar 9. [Epub ahead of print]
[h=1]Targeting PI3K-p110α Suppresses Influenza Viral Infection in Chronic Obstructive Pulmonary Disease.[/h] Hsu AC[SUP]1[/SUP], Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, Barr I, Mahony JB, Foster PS, Knight DA, Wark PA, Hansbro PM.
[h=3]Author information[/h]
[h=3]Abstract[/h] Rationale: Chronic obstructive pulmonary disease (COPD) and influenza viral infections are major global health issues. COPD patients are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD, and the potential for therapeutic targeting. Methods: We utilized a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and main results: COPD pBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity; reduced retinoic acid-inducible gene-I (RIG-I), interferon (IFN)/cytokine and chemokine responses. Increased PI3K-p110α levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110α inhibitors or exogenous IFN-β restored protective antiviral responses, suppressed infection and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which is mediated by increased PI3K-p110α activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks, to prevent and/or treat influenza.
[h=4]KEYWORDS:[/h] COPD; Influenza; Innate Immunity; PI3K
PMID: 25751541 [PubMed - as supplied by publisher]
[h=1]Targeting PI3K-p110α Suppresses Influenza Viral Infection in Chronic Obstructive Pulmonary Disease.[/h] Hsu AC[SUP]1[/SUP], Starkey MR, Hanish I, Parsons K, Haw TJ, Howland LJ, Barr I, Mahony JB, Foster PS, Knight DA, Wark PA, Hansbro PM.
[h=3]Author information[/h]
[h=3]Abstract[/h] Rationale: Chronic obstructive pulmonary disease (COPD) and influenza viral infections are major global health issues. COPD patients are more susceptible to infection, which exacerbates their condition and increases morbidity and mortality. The mechanisms of increased susceptibility remain poorly understood, and current preventions and treatments have substantial limitations. Objectives: To characterize the mechanisms of increased susceptibility to influenza virus infection in COPD, and the potential for therapeutic targeting. Methods: We utilized a combination of primary bronchial epithelial cells (pBECs) from COPD and healthy control subjects, a mouse model of cigarette smoke-induced experimental COPD and influenza infection. The role of the phosphoinositide-3-kinase (PI3K) pathway was characterized using molecular methods, and its potential for targeting assessed using inhibitors. Measurements and main results: COPD pBECs were susceptible to increased viral entry and replication. Infected mice with experimental COPD also had more severe infection (increased viral titer and pulmonary inflammation, and compromised lung function). These processes were associated with impaired antiviral immunity; reduced retinoic acid-inducible gene-I (RIG-I), interferon (IFN)/cytokine and chemokine responses. Increased PI3K-p110α levels and activity in COPD pBECs and/or mice were responsible for increased infection and reduced antiviral responses. Global PI3K, specific therapeutic p110α inhibitors or exogenous IFN-β restored protective antiviral responses, suppressed infection and improved lung function. Conclusions: The increased susceptibility of individuals with COPD to influenza likely results from impaired antiviral responses, which is mediated by increased PI3K-p110α activity. This pathway may be targeted therapeutically in COPD, or in healthy individuals, during seasonal or pandemic outbreaks, to prevent and/or treat influenza.
[h=4]KEYWORDS:[/h] COPD; Influenza; Innate Immunity; PI3K
PMID: 25751541 [PubMed - as supplied by publisher]