Influenza A virus is a significant cause of morbidity and mortality worldwide. Severe influenza is recognized as a clinical syndrome, characterized by hyperinduction of proinflammatory cytokine production, otherwise known as hypercytokinemia or a 'cytokine storm'. Research focused on therapeutics to modulate influenza virus-induced inflammation is currently underway. In this review, we discuss the limitations of current antiviral drug treatment strategies, describe the influenza viral and host pathogenicity determinants, and present the evidence supporting the use of immunomodulatory therapy to target the host inflammatory response as a means to improve clinical outcome in severe influenza. We then review the experimental data on investigational immunomodulatory agents targeting the host inflammatory response in severe influenza, including anti-TNF therapy, statins, glucocorticoids, cyclooxygenase-2 inhibitors, macrolides, peroxisome proliferator-activated receptor agonists, AMP-activated protein kinase agonists and high mobility group box 1 antagonists. We then conclude with a rationale for the use of mesenchymal stromal (stem) cells and angiopoietin-1 therapy against deleterious influenza-induced host responses that mediate end-organ injury and dysfunction.
The development of severe influenza has been attributed, in part, to a heightened innate immune response. Recent evidence suggests that endothelial activation, loss of barrier function, and consequent microvascular leak may also serve important mechanistic roles in the pathogenesis of severe influenza. The aim of this review is to summarize the current evidence in support of endothelial activation and dysfunction as a central feature preceding the development of severe influenza. We also discuss the effect of influenza on platelet–endothelial interactions.
RationaleSevere influenza remains a major public health threat and is responsible for thousands of deaths annually. Increasing antiviral resistance and limited effectiveness of current therapies highlight the need for new approaches to influenza treatment. Extensive pre-clinical data have shown that mesenchymal stromal (stem) cell (MSC) therapy can induce anti-inflammatory effects and enhance repair of the injured lung. We hypothesized that MSC therapy would improve survival, dampen lung inflammation and decrease acute lung injury (ALI) in a murine model of severe influenza. MethodsC57Bl/6 mice were infected with influenza A/PuertoRico/8/34 (mouse-adapted H1N1) or influenza A/Mexico/4108/2009 (swine-origin pandemic H1N1) and administered human or mouse MSCs via the tail vein, either pre- or post- infection. MSC efficacy was evaluated as both an independent and adjunctive treatment strategy in combination with the antiviral agent, oseltamivir. Weight loss and survival were monitored. Inflammatory cells, cytokine/chemokines (IFN-γ, CXCL10, CCL2 and CCL5) and markers of ALI (total protein and IgM), were measured in bronchoalveolar lavage fluid and lung parenchyma.ResultsAdministration of murine MSCs or human MSCs in a prophylactic or therapeutic regimen failed to improve survival, decrease pulmonary inflammation/inflammatory cell counts or prevent ALI in influenza virus-infected mice. MSCs administered in combination with oseltamivir also failed to improve outcomes.ConclusionsDespite similarities in the clinical presentation and pathobiology of ALI and severe influenza, our findings suggest that MSC therapy may not be effective for prevention and/or treatment of acute severe influenza.
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