Proposed mechanism of halothane (HAL) type I interferon (IFN) modulation during flu and secondary bacterial pneumonia. The influenza virulence factor, NS1, delays epithelial cell (white rhomboid, brown nucleus) type I IFN production in response to viral nucleic acids until day 5 postviral infection (PVI). (A) In the absence of HAL exposure, the full effects of this delayed type I IFN (IFN-α) expression on both innate (phagocytic alveolar macrophages, yellow stars) and adaptive cells (lymphocytes, purple) are unopposed. (B) After HAL exposure, the effects of delayed type I IFN are effectively blocked, without altering the type I IFN expression levels. This renders cells of the immune system less susceptible to phenotypic alteration because of this cytokine. (C) At day 6 PVI, 3 h postbacterial infection (PBI), immune cells exhibit altered phenotypes as a result of type I IFN and lack of HAL exposure that would dampen these effects of type I IFN. This results in enhanced lymphocyte production of IFN-γ, decreased phagocytic activity of macrophages, and enhanced recruitment of inflammatory monocytes (red) through MCP-1 production. All these factors result in increased bacterial infection (blue ovals) and pulmonary damage. (D) HAL-mediated blockade of the effects of type I IFN results in reduced IFN-γ production, maintenance of phagocytic macrophage activity, decreased inflammatory monocyte recruitment, and preferential recruitment of neutrophils (green) through KC/MIP-2 expression after bacterial challenge postflu. This results in bacterial clearance and decreased pulmonary damage. KC = keratinocyte-derived chemokine; MCP-1 = monocytic chemotactic protein-1; MIP-2 = macrophage inflammatory protein-2.