Invited commentary on David Fedson’s article

نویسندگان

  • Ian Clark
  • Lisa Alleva
چکیده

The recent H5N1 and H1N1 scares demonstrate that political, bureaucratic, and to a large extent scientific, thinking about how to ward off potentially large fatalities is currently restricted to stockpiling antivirals and generating new vaccines. Nevertheless, as David Fedson pointed out with undeniable logic in last month’s issue of this journal (3: 129–142), an influenza research community that continues to confine its efforts to these approaches will fall far short, in any severe pandemic, in its brief to prevent worldwide high mortality. Central to Fedson’s answer to this challenge is for us to examine more closely the argument that a fatal outcome in influenza is largely a manifestation of excessive release of inflammatory cytokines, as embodied in the cytokine concept of disease. Given reasonable acceptance of this, he argues, we should then put more effort into testing the potential for treating influenza illness with cheap and readily available agents that are already, on other rationales, in therapeutic use for other purposes, and also known to suppress production of disease-inducing cytokines. What is the cytokine concept of disease, and how wide is its relevance across the infectious diseases? The idea began nearly 30 years ago when a newly described endogenous anti-tumour agent was used to rationalise the nature of malaria and systemic bacterial infections. As reviewed, when rTNF was later being tested as an anti-tumour agent in patients, the toxicity that prevented its widespread use so strikingly mimicked influenza that tumour researchers referred, in print, to it generating influenza-like side effects. Symptoms, which included fatigue, fever, anorexia, chills, headache, pulmonary oedema, immunosuppression, myalgia, nausea, vomiting and diarrhoea were worse with higher doses. Parenteral interleukin-2, by inducing TNF, also produces a very similar clinical picture. Together with influenza being the standard misdiagnosis of imported malaria in temperate countries, the experiences of these tumour researchers made it plausible that this disease model would explain the pathology of viral diseases, including influenza, as well as that of malaria and bacterial sepsis. The concept of cytokine excess has also been adopted to rationalise the diseases caused by Mycobacterium spp., Salmonella typhi, Leishmania spp., Toxoplasma gondii, Coxiella brunetii, and Listeria monocytogenes. It dominates the literature on the pathophysiological consequences of trauma, haemorrhagic shock, and burns because these, too, originate from cytokine excess. Different triggers (gram-negative lipopolysaccharide, gram positive toxins, fungal or malarial toxins, or modulation of RIG-1 gene expression) and sites of production can be expected to generate different local patterns, so we must expect some clinical and pathological dissimilarities between systemic diseases that share this common fundamental origin. TNF generation and circulating levels are increased in influenza, particularly so for influenza caused by the more pathogenic strains. The evidence linking the excess cytokine concept with influenza disease will be well-known by most readers. In brief, influenza A virus stimulates the release of TNF from macrophages, and the recent avian strain induces production of more TNF from human macrophages than do a range of less virulent strains of human influenza. Likewise, this H5N1 influenza virus induces an inflammatory cytokine response in primary cultures of human alveolar and bronchial epithelial cells. H5N1 ⁄ 97 upregulates TNF mRNA levels and TNF-related apoptosisinducing ligand (TRAIL) in human monocyte-derived macrophages, and higher levels of inflammatory cytokines and chemokines are associated with a fatal outcome. Moreover, a reconstructed version of the strain of influenza virus responsible for massive human mortality in 1918–1919, but not non-virulent constructs or strains, induces a strong and prolonged pro-inflammatory cytokine response during the fatal infections it causes in mice 23 and macaque monkeys. The literature’s emphasis on TNF may be artificial, but it is now accepted as the progenitor of a cytokine superfamily, and is demonstrated to be a master regulator of the network of mediators it induces and interacts with. Thus Fedson’s proposal – that any agent known to reduce inflammatory cytokine production and to ameliorate any one of the diseases or conditions mentioned earlier warrants testing in the others – is logical and compelling. Examples are two peroxisome proliferator-activated receptor (PPAR) agonists: gemfibrozil, a fibrate (PPAR-a agonist), reported DOI:10.1111/j.1750-2659.2009.00098.x www.blackwellpublishing.com/influenza Invited Commentary

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عنوان ژورنال:

دوره 3  شماره 

صفحات  -

تاریخ انتشار 2009