Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza

Abstract

It is now accepted that an overwhelming inflammatory response is the cause of human deaths from avian H5N1 influenza infection. With this in mind we sought to examine the literature for examples of complementary and alternative medicines that reduce inflammation, and to place the results of this search in the context of our own work in a mouse model of influenza disease, using a pharmaceutical agent with anti-inflammatory properties. Two Chinese herbs, Angelica sinensis (Dang Gui) and Salvia miltiorrhiza (Danshen), have been recently shown to protect mice during lethal experimental sepsis via inhibition of the novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1). Biochanin A, a ligand of the peroxisome proliferator activated receptors (PPAR) alpha and gamma and the active isoflavone in Trifolium pratense (red clover), has anti-inflammatory properties, and thus could be used as an influenza treatment. This is of great interest since we have recently shown that gemfibrozil, a drug used to treat hyperlipidemia in humans and a synthetic ligand of PPAR alpha, significantly reduces the mortality associated with influenza infections in mice. The inflammation-modulating abilities of these natural agents should be considered in light of what is now known about the mechanisms of fatal influenza, and tested as potential candidates for influenza treatments in their own right, or as adjunct treatments to antivirals.

Figure 1.

Amplification and prolongation of inflammation by high mobility group box 1 protein (HMGB1) during influenza. Influenza virus-infected airway epithelial cells may passively release HMGB1 [see ref. (92) as an example], while alveolar macrophages, which become infected with influenza virus (93), secrete pro-inflammatory cytokines and may also secrete HMGB1 both actively and passively. MIP is macrophage inflammatory protein. Cytokines (excluding IL-10) commonly reported to be involved in pathogenesis were compiled from (94–96). IL-10 from effector T-cells was recently shown to limit inflammation during acute influenza (97). HMGB1 up-regulates pro-inflammatory cytokine expression via its cellular receptors, the receptor for advanced glycation end products [RAGE; (41,42,98)] and to a lesser extent, toll-like receptor (TLR) 2 and 4 (43,99). RAGE expression was recently shown to be associated with influenza A virus pneumonia, accompanied by increased levels of HMGB1 in bronchoalveolar lavage fluid (100).

Figure 2.

Potential mitigation of the action of HMGB1 and other pro-inflammatory cytokines by traditional Chinese medicines, a natural agent, and pharmaceutical drugs. The Chinese medicine glycyrrhizin, from liquorice root, binds to HMGB1 and inactivates its biological activities (34), while the Chinese herbs A. sinensis and S. miltiorrhiza reduce the release of HMGB1 (37,46). Release of pro-inflammatory cytokines is reduced via inhibition of NF-κB activation, by glycyrrhizin (101–103), A. sinensis (104,105), and S. miltiorrhiza (106,107); by the natural agent biochanin A (65,108,109); and the pharmaceutical drugs statins (110,111) and fibrates (21,112,113). Pro-inflammatory cytokine release is reduced by activation of PPARs (21) and conversely, anti-inflammatory cytokine release is increased by their activation (114,115). PPAR alpha is activated by fibrates (21); PPAR alpha and gamma are activated by biochanin A (64); and statins upregulate PPAR alpha and gamma and show molecular signaling properties similar to fibrates (116).