Bacterial pneumonia is a frequent complication of acute lung injury. The prototypical example is the secondary pneumonia that often follows influenza, and which is a major cause of deaths from both seasonal and epidemic flu. A critical cause of post-injury susceptibility is well known: the lung's 1st responder cell, the alveolar macrophage (AM), has profoundly diminished antibacterial function after influenza or other lung injuries. What is missing are novel, mechanism-based therapeutics to enhance AM host defense function during such high-risk periods. Our proposal focuses on the normal human protein, plasma gelsolin (pGSN), and its potential to be a novel immunomodulator that can reduce risk of pneumonia. Pilot studies with the common pathogen Strep. pneumoniae indicate that pGSN rapidly improves macrophage bacterial killing in vitro, and that aerosolized pGSN improves bacterial clearance in vivo. Additional clues to the mechanism implicate activation of lung macrophage nitric oxide synthase 3 (NOS3), highlighted by loss of beneficial effects of pGSN when added to NOS3 -/- macrophages. The two main goals of this project are: 1) to assess the potential of pGSN to improve lung host defense after the prototypical lung injury caused by influenza; 2) to characterize the mechanisms by which pGSN enhances AM antibacterial function.
Aim 1 will determine the role of plasma gelsolin in host defense against pneumonia in vivo. These studies will use a model of non-lethal influenza with enhanced susceptibility to secondary pneumococcal pneumonia during the resolution phase. We will characterize changes in pGSN levels and function in the lung that follow acute lung injury, and we will test the effect of prophylactic treatment with pGSN on bacterial clearance and survival of the secondary pneumonia challenge.
Aim 2 will characterize mechanisms by which plasma gelsolin enhances AM anti-bacterial function. The postulated role for AM NOS3 will be tested using in vitro assays of pGSN enhancement of bacterial killing, NOS inhibitors and AMs from NOS3 -/- mice, and evaluation of signaling pathways for activation of NOS3 through Akt phosphorylation cascades. We will also investigate whether plasma gelsolin functions by delivering signaling phospholipids present in lung fluids and known to activate NOS3, e.g. sphingosine-1-phosphate to its receptor (S1PR1), through binding and competition assays, and use of S1P receptor knockout mice and cells. The proposal addresses a major cause of morbidity and mortality after influenza and other acute lung injuries, and will evaluate an endogenous immunomodulator with great potential for translation into therapeutic benefit.
The proposal addresses a major cause of morbidity and mortality after influenza and other acute lung injuries, and will evaluate an endogenous immunomodulator with great potential for translation into therapeutic benefit.
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