Abstract
Purpose: :
Cigarette smoke is the single greatest environmental risk factor for age–related macular degeneration, and the effects of smoking are partially retained years after cessation. We have shown that cigarette smoke causes more severe CNV in mice. One proposed mechanism for the long lasting effect of smoke is toxic damage to vascular cells or extracellular matrix in blood vessels, which would persist long after smoke cessation. Another possibility is smoke–related alterations in myeloid or vascular progenitors in the marrow. In this case, the long term consequences of smoke would be retained in the bone marrow, but not in the peripheral tissue. We performed an experiment to test this distinction.
Methods: :
We performed bone marrow transplantation (BMT) by isolating bone marrow from mice exposed to full stream cigarette smoke two hrs daily for four weeks transferred into normal, non–exposed recipients; or vice versa, marrow from non–exposed mice into smoke–exposed recipients. Then, laser–induced–CNV was created.
Results: :
Mice exposed to cigarette smoke demonstrated typically large CNV compared to normal controls without smoke exposure. Normal mice receiving normal bone marrow demonstrated typical small lesions. However, normal mice receiving BMT from smoke–exposed donors demonstrated large CNV, similar to the CNV in mice actively exposed to smoke (n=6, 2.5±0.3 Disc areas (DA) for normal receiving normal marrow v. 3.8±0.8 DA for normal receiving smoked marrow, p<0.01). In contrast, in the inverse experiment, mice that received four weeks of smoke exposure prior to BMT, then reconstituted with normal marrow, demonstrated no difference in size of CNV from control mice (n=6, 2.5±0.3 DA for normal receiving normal marrow v. 2.6±0.5 DA for smoked mice receiving normal marrow, p=ns).
Conclusions: :
Cigarette smoke mediates a major part of its effect on CNV by unknown mechanisms on bone marrow cells, not upon vascular cells or resident monocytes in the choroid. Two possibilities exist: smoke alters the function of myeloid precursors, such that BMT transfers myeloid precursors destined to become activated blood–derived macrophages with preferential recruitment into CNV; and/or the alternative, smoke alters vascular precursor biology, such that the effect of smoke resides in the vascular precursor cell subset in the marrow.
Keywords: age-related macular degeneration • choroid: neovascularization