title: A Targeted Inhibitor of the Alternative Complement Pathway Accelerates Recovery From Smoke-Induced Ocular Injury.
abstract: OBJECTIVE
  Morphologic and genetic evidence exists that an overactive complement system driven by the complement alternative pathway (AP) is involved in pathogenesis of age-related macular degeneration (AMD). Smoking is the only modifiable risk factor for AMD. As we have shown that smoke-related ocular pathology can be prevented in mice that lack an essential activator of AP, we ask here whether this pathology can be reversed by increasing inhibition in AP.
  
  
  METHODS
  Mice were exposed to either cigarette smoke (CS) or filtered air (6 hours/day, 5 days/week, 6 months). Smoke-exposed animals were then treated with the AP inhibitor (CR2-fH) or vehicle control (PBS) for the following 3 months. Spatial frequency and contrast sensitivity were assessed by optokinetic response paradigms at 6 and 9 months; additional readouts included assessment of retinal morphology by electron microscopy (EM) and gene expression analysis by quantitative RT-PCR.
  
  
  RESULTS
  The CS mice treated with CR2-fH showed significant improvement in contrast threshold compared to PBS-treated mice, whereas spatial frequency was unaffected by CS or pharmacologic intervention. Treatment with CR2-fH in CS animals reversed thinning of the retina observed in PBS-treated mice as analyzed by spectral-domain optical coherence tomography, and reversed most morphologic changes in RPE and Bruch's membrane seen in CS animals by EM.
  
  
  CONCLUSIONS
  Taken together, these findings suggest that AP inhibitors not only prevent, but have the potential to accelerate the clearance of complement-mediated ocular injury. Improving our understanding of the regulation of the AP is paramount to developing novel treatment approaches for AMD.
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Woodell
authors.affiliation: Moran Eye Center, University of Utah, Salt Lake City, Utah, United States.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Jones
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Tucker
authors.initials: T
authors.lastname: Williamson
authors.affiliation: Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States.
authors.forename: Gloriane
authors.initials: G
authors.lastname: Schnabolk
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States 4Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States 5Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.affiliation: Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, United States 4Research Service, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States 6Department of Ophthalmology, Medical University o.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Rohrer
mesh_terms: D000818:Animals; D003170:Complement Pathway, Alternative / Q000187:drug effects / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D005786:Gene Expression Regulation; D008268:Macular Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D020127:Recovery of Function; D012160:Retina / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012906:Smoke / Q000009:adverse effects*; D014792:Visual Acuity / Q000502:physiology
chemical_list: C000597269:CR2-fH protein; D011993:Recombinant Fusion Proteins; D012906:Smoke; D004247:DNA