Drugs to cure avian influenza infection--multiple ways to prevent cell death

Abstract

New treatments and new drugs for avian influenza virus (AIV) infection are developed continually, but there are still high mortality rates. The main reason may be that not all cell death pathways induced by AIV were blocked by the current therapies. In this review, drugs for AIV and associated acute respiratory distress syndrome (ARDS) are summarized. The roles of antioxidant (vitamin C) and multiple immunomodulators (such as Celecoxib, Mesalazine and Eritoran) are discussed. The clinical care of ARDS may result in ischemia reperfusion injury to poorly ventilated alveolar cells. Cyclosporin A should effectively inhibit this kind of damages and, therefore, may be the key drug for the survival of patients with virus-induced ARDS. Treatment with protease inhibitor Ulinastatin could also protect lysosome integrity after the infection. Through these analyses, a large drug combination is proposed, which may hypothetically greatly reduce the mortality rate.

Figure 1

Summary of therapies, mortality rates and the therapeutic mechanisms. AIV, avian influenza virus; ARDS, acute respiratory distress syndrome; mt, mitochondrion; ROS, reactive oxygen species; CsA, cyclosporin A

Figure 2

Possible IR injury during clinical care of ARDS. (a) Normal ventilation–perfusion matching. (b) HPV. (c) Upon HPV, mechanical ventilation and high-flow oxygen therapy may restore the oxygen supply to the poorly ventilated alveolar cells (with the possible occurrence of IR injury). (d) Corticosteroid treatment and inhaled NO administration may restore the blood supply to the poorly ventilated alveolar cells (with the possible occurrence of IR injury). (e) Mismatching of blood flow and alveolar ventilation results in hypoxemia. (f) Upon a mismatch, mechanical ventilation and high-flow oxygen therapy may restore the oxygen supply to the poorly ventilated alveolar cells (with the possible occurrence of IR injury). (g) Upon a mismatch, corticosteroid treatment and inhaled NO administration may restore the blood supply to the poorly supplied but well-ventilated alveolar cells (with the possible occurrence of IR injury). (h) Cell death may ultimately result in ARDS care failure and organ death. CsA may inhibit this IR injury and alveolar damages

Figure 3

Model of the therapeutic mechanisms at the subcellular level. AIV-induced biochemical changes and cell death pathways are marked in red color. Potential targets of the drugs are marked in green color. AIV, avian influenza virus; Bcl-2, B-cell lymphoma 2; CAT, catalase; CsA, cyclosporin A; Cyt c, cytochrome c; MBCNI, mechanism-based covalent neuraminidase inhibitors; mPT, mitochondrial permeability transition; ROS, reactive oxygen species; SOD, superoxide dismutase; TNFα, tumor necrosis factor-α; VC, vitamin C