RT Journal Article SR Electronic T1 The TNF-derived TIP peptide reduces lung dysfunction in experimental influenza A virus infection JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1702 VO 38 IS Suppl 55 A1 Rudolf Lucas A1 Guang Yang A1 Supriya Sridhar A1 Zachary Traylor A1 Hamid Hossain A1 Bernhard Fischer A1 Trinad Chakraborty A1 Ian Davis YR 2011 UL http://erj.ersjournals.com/content/38/Suppl_55/1702.abstract AB Background: Permeability edema during Influenza A virus (IAV) infection is characterized by reduced alveolar liquid clearance (ALC) and pulmonary endothelial hyperpermeability. Mortality after IAV infection is mainly due to secondary pneumococcal infections and occurs after antibiotic therapy, which can release the toxin pneumolysin (PLY) in the lungs.Aims: To investigate whether the TNF-derived TIP peptide, which reduces PLY-induced edema, can blunt IAV-induced ALC dysfunction and combined IAV/PLY-induced barrier dysfunction.Methods: ALC is assessed in BALB/c mice infected i.n. for 2d with 10,000 FFU/mouse (strain H1N1-A/WSN/33), using the BSA dilution method. We measure IAV/PLY-induced changes in transendothelial resistance (TER) in monolayers of human lung microvascular endothelial cells (HL-MVEC; ECIS).Results: IAV infection reduces basal ALC by 50±5%, which is prevented by co-instillation of the TIP peptide (2.5 mg/kg; n=11). The combination of PLY (7.5 ng/ml) and UV-inactivated IAV (1 virus/cell) causes a significant drop in normalized TER in HL-MVEC monolayers from 100 to 40±3% of baseline. The TIP peptide (50 μg/ml), as well as Ro32-4032 (10 nM), a specific inhibitor of PKC-α, implicated in both ALC dysfunction and hyperpermeability, restore TER to 86±4 and 80±6% of ctrl, respectively (n=4). IAV-treatment increases PKC-α activation by 110±7% over basal in HL-MVEC, an effect significantly blunted by the TIP peptide (23±1% over basal, n=4).Conclusions: The TIP peptide represents a therapeutic candidate for the treatment of IAV-associated lung dysfunction, since it interferes with both IAV infection-associated ALC and barrier dysfunction, upon reducing PKC-α activation.