By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, Associate Editor of Infectious Disease Alert. Dr. Winslow is a consultant for Siemens Diagnostic.
Synopsis: High levels of circulating leptin contribute to the development of severe lung injury by Influenza A(H1N1) pdm09 in mice with diet-induced obesity.
Source: Zhang AJX, et al Leptin mediates the pathogenesis of severe 2009 pandemic influenza A (H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity. JID 2013; 207: 1270-80.
In a mouse model of diet-induced obesity obese mice infected with pandemic influenza A (H1N1) (pdm09) had significantly higher pulmonary viral titers and mortality compared with age-matched lean mice. Obese mice had heightened proinflammatory cytokine and chemokine levels and more severe pulmonary damage and this was associated with higher preexisting serum leptin levels and lower adiponectin levels. Recombinant leptin increased IL-6 mRNA in single-lung-cell preparations. Administration of anti-leptin antibody improved survival in obese mice and was associated with reductions in pulmonary levels of the pro-inflammatory cytokines IL-6 and IL-1B, but did not affect pulmonary viral titer.
During the 2009 influenza pandemic, obesity was unexpectedly seen to be an independent risk factor which increased the likelihood of hospitalization, admission to the ICU, and death. The mechanisms responsible for this association are not clear. The adipokines leptin and adiponectin are known to regulate the inflammatory response and leptin is pro-inflammatory and is associated with chronic systemic inflammation in obese individuals. In addition to being secreted by adipose tissue, leptin is secreted by bronchial epithelial cells, type II pneumocytes and lung macrophages. Higher leptin levels in bronchoalveolar fluid have been associated with higher mortality in patients with acute respiratory distress syndrome.1,2 Other studies have shown that higher leptin levels are associated with more severe asthma and COPD.3,4
This study conducted in a mouse model of obesity induced by diet sheds some light on possible pathogenic mechanisms responsible for the severity of pandemic influenza A seen in obese patients. It seems likely that the pro-inflammatory effect of leptin (likely mediated by increased transcription of inflammatory cytokines by lung macrophages and epithelial cells) is causal. In addition, the low levels of the anti-inflammatory cytokine adiponectin (which induces production of the anti-inflammatory cytokines IL-10 and Il-1 receptor antagonist) may contribute to the severity of disease as well.
While these mouse studies must be extrapolated carefully to human disease, the effectiveness of anti-leptin antibody in reducing mortality (without decreasing pulmonary viral load) in mice suggests that modulation of the immune response in severe influenza may improve survival in obese patients with influenza, especially in patients who present more than 48 hours after symptom onset when antiviral treatment may be less effective.
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2. Jain M, et al. Leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferation-activated receptor-gamma. Am J Respir Crit Care Med 2011; 183: 1490-8.
3. Vernooy JH, et al. Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers. Thorax 2009; 64: 26-32.
4. Al Assad N, Sood A. Leptin, adiponectin and pulmonary diseases. Biochimie 2012; 94: 2180-9.