Ivan J. Suñer, MD
Scott W. Cousins, MD
Durham, N.C.

As age-related macular degeneration primarily affects the macula, it has a severe impact on many of the basic ac­tivities of daily living such as driving, recognizing faces and reading. Therefore, it robs af­fected in­dividuals of their independence in their retirement years. Fif­teen million people in the United States alone are affected by AMD, and current estimates project this figure to increase by 50 percent by the year 2020. Ap­proximately 1.75 million (10 percent) Am­er­icans have the advanced or late forms of the dis­ease, exudative/wet AMD and geographic atrophy.1

Epidemiology of Smoking and AMD

AMD is a multifactorial disease with associated age, environmental, sys­tem­ic and genetic factors. Age is the major risk factor in AMD. The prevalence of all forms of AMD increases significantly with age. It affects approximately 17 percent of all individuals between the ages of 55 and 64, and the prevalence rises to approximately 37 percent in those 75 or older.2 The more ad­vanced, disabling forms (ex­uda­tive/wet and geographic atrophy) affect 1 percent of Cau­casian patients in their 50s, rising to more than 15 percent of those in their 80s.1

Figure 1. Representative transmission electron micrographs (TEM) of outer retina and choroid in 16-month-old female mice demonstrating dry AMD findings in mice exposed to cigarette smoke or hydroquinone, a major component of cigarette tar. Panel A. TEM of mouse fed high fat diet without exposure to cigarette smoke or hydroquinone; specimen shows mild nodular sub-RPE deposits (white arrows); Bruch's membrane and choriocapillaris are normal thickness. Panel B. TEM of mouse fed high-fat diet and exposed to cigarette smoke; there are sub-RPE deposits (white arrows) and thickening of Bruch's membrane with accumulation of a homogenous material (white asterisk). Panel C. TEM of mouse fed high-fat diet plus hydroquinone; there are thick sub-RPE deposits (white asterisks) and marked thickening of Bruch's membrane (white arrows). 

Cigarette smoking is the single most important modifiable environmental risk factor for development of all forms of AMD. Multiple large, well-controlled, cross-sectional3-6 and prospective7,8 studies in the United States, Australia, France and the Neth­erlands have demonstrated a 2.5- to threefold increase in the risk of all forms of AMD in smokers. Of particular interest is an analysis of pooled data from cross-sectional studies carried out in North Am­erica, Eu­rope and Australia. This data shows an es­pecially large disparity between cur­rent and never smokers with a threefold increase in all forms of AMD, 2.5-fold increase in atrophic AMD, and 4.5-fold increase in neovascular AMD9 (See Table 1).

Figure 2. Representative flatmount preparation (propidium iodide stain) of the posterior pole of 11-month-old mouse eyes 4 weeks after laser treatment.  Four laser spots centered on the optic nerve (D) were performed. Panel A. Control group. CNV lesions were small and circular with discrete borders (dotted lines). Panel B. Oral nicotine group. In this example there is coalescence of three laser injuries gives rise to a large CNV complex (dotted lines). Panel C. Oral nicotine and subconjunctival hexamethonium group. A reduction of the severity of CNV lesions can be clearly appreciated with concurrent administration of a nicotine antagonist, hexamethonium. CNV lesions (dotted line) were similar in size to the control.

An important factor, yet difficult to tease out of this association, is the in­fluence of pack years, current smoking status, ex-smoker and passive smoker. A recent study looked at these issues specifically.10 It demonstrated a strong association between AMD and number of pack years smoked. The odds ratio in patients smoking greater than 40 pack years was 2.75 as compared to nonsmokers; the odds ratio was 3.43 for geographic atrophy and 2.49 for choroidal neovascularization. Smoke cessation was associated with decreasing risk, reaching a similar risk to nonsmokers at 20 years of not smoking. Pas­sive smoking was associated with an odds ratio of 1.87.

An interesting observation is the trend towards earlier onset of AMD, including advanced forms, in Asian countries. This has been attributed in large part to the increased rates of smoking and environmental pollutants.11


Why Study Smoking and AMD?

Despite the wealth of robust epidemiologic evidence associating smoking with AMD, there is a relative dearth of science to support it. Only now are we beginning to study and elucidate pathobiologic mechanisms of this association. This may be partly due to the concept that cigarette smoking is considered purely a modifiable risk factor. In other words, pa­tients with AMD should quit smoking, and, therefore, there is not more to be gained by further pursuing this association on a biologic level. However, studying the effects of smoking on AMD may provide us with insights into the pathobiology of this complex disease process. Furthermore, some of the lessons we learn may translate into therapies for smokers as well as for nonsmokers.


Composition of Cigarette Smoke

Cigarette smoke is a complex mixture of more than 4,000 chemical substances. Selecting which molecules to study within the daunting number of potential candidates is a difficult issue. The agents present in cigarette smoke are generally subdivided into particulate and gaseous phases.12 The major components of the particulate phase are tar and nicotine, whereas the gas­eous phase is composed primarily of carbon monoxide, carbon dioxide and nitric oxide.

Various proposed mechanisms by which cigarette smoke may cause end-organ damage include direct effects from chemicals in the smoke, immune activation, secondary hypoxia from pulmonary damage, and secondary sequelae from smoking-induced vascular disease.

Dry AMD and Smoking

The exact pathogenesis of drusen remains an unresolved question. One paradigm, "the response to injury" hy­pothesis, proposes that the RPE cell is the target for specific injury stimuli, resulting in deposit accumulation.13

Cigarette smoke tar contains nu­merous pro-oxidant compounds within the quinone family.14 Within these, hydroquinone, a benzene derivative, is the most abundant quinone in cigarette tar. High levels are detected in the plasma and urine of smokers.14

Our group tested this hypothesis in cultured human RPE cells. In­cu­bation of RPE cells with hydroqui­none induced a specific injury re­sponse called nonlethal blebbing, a process that is proposed to be related to sub-RPE deposit formation.15 Fur­thermore, exposure to hydroquinone also resulted in decreased levels of matrix metalloproteinase-2 and in­creased levels of collagen IV as measured by zymography (Suñer I, et al. In­vest Ophthalmol Vis Sci. 2004;45: ARVO E-Abstract 1810). This leads to a net decrease in extracellular matrix turnover, which would result in thickening of Bruch's membrane or formation of sub-RPE deposits.

This relationship was further studied in an animal model by exposing mice to whole cigarette smoke or oral hydroquinone. In mice fed a high-fat diet and exposed to either cigarette smoke in a smoking chamber or di­et­ary hydroquinone, Bruch's membrane was thickened and sub-RPE deposits developed in contrast to controls only receiving a high-fat diet (See Figure 1).16 Therefore, smoke-related oxi­dants, specifically tar, ap­pear to be a significant oxidative in­jury stimulus that leads to dry AMD in the context of other oxidative sources such as high-fat diet or blue light. It is also likely that while tar is a po­tent oxidant within cigarette smoke, it is not the only oxidant molecule in this pathway.


Wet AMD and Smoking

Nicotine is an attractive candidate molecule to explain an association of smoking with wet AMD. It has been shown to be mitogenic for vascular endothelial cells and smooth muscle pericytes, to reduce apoptosis of vascular endothelial cells, and to induce the formation of capillary tubes.17,18

We explored the effects of nicotine in a laser model for CNV in mice. We compared CNV size in those receiving nicotine in the drinking water or cigarette smoke in a smoking chamber with control animals. Mice receiving nicotine or cigarette smoke had a statistically significant increase in CNV size (twice the di­ameter in aged mice). This effect was blocked by subconjunctival coadministration of a nonspecific nicotinic antagonist, hexamethonium (See Figure 2).17

The experiment was carried one step further, and bone-marrow transplantation was performed within the CNV mouse model. Mice that were exposed to cigarette smoke in a smoking chamber and subsequently had bone marrow ablation followed by bone marrow reconstitution from a control mouse had regression of CNV to control levels. Conversely, a control mouse receiving bone marrow from a cigarette smoke-exposed mouse de­monstrated increased CNV size com­parable to cigarette smoke-ex­posed mice (Cousins S, et al. Invest Oph­thalmol Vis Sci. 2006;47:ARVO E-Ab­stract 4172). This suggests that bone marrow-derived cells, either endothelial or inflammatory precursor cells, may play a role in establishing or modulating choroidal neovascularization.

Immunohistochemical analysis of CNV in cigarette smoke-exposed or nicotine-exposed mice reveals an in­creased number of macrophages in these lesions as compared to controls. Furthermore, it demonstrated higher le­vels of macrophages expressing TNF-a and COX-2 (Suñer I, et al. In­vest Ophthalmol Vis Sci. 2006;47: ARVO E-Abstract 1531). These are markers of activated macrophages, which supports current theories of in­flam­matory contributions to the path­ogenesis of AMD.

Clinical Implications

The immediate clinical implications of these findings are that we must continue to impress upon our patients that smoking is not only a significant risk factor for cancer, heart disease and pulmonary disease, but that it is the leading modifiable risk factor for the leading cause of blindness in pa­tients older than 50 years of age. It appears that risks correlate with total number of pack years, and that smoke cessation may result in risk reduction to that of never smokers at 20 years. Fur­thermore, second hand smoke also confers risk for AMD.

Dry AMD patients should be en­couraged to quit smoking. Those with higher-risk lesions per the Age-Re­lated Eye Disease Study should take the recommended vitamin supplementation with the exception of ß-ca­ro­tene, which has been demonstrated to increase rates of lung cancer.20

Patients with active choroidal neovascularization should be especially encouraged to quit smoking. Fur­thermore, they should abstain from nicotine replacement therapies as nicotine may promote growth of the lesion.


Future Directions

We are entering an era of molecular therapies for retinal diseases. As we learn more about the pathobiologic mechanisms by which smoking im­pacts AMD, we may discover specific pathways of oxidation or im­mu­no­modulation in dry AMD and of vascular endothelial cell and smooth-muscle pericyte proliferation, matrix turnover or immunomodulation that are relevant to wet AMD.

It is also likely that these pathways will be relevant to the biology of AMD not only in smokers, but also nonsmokers. Taking the example of nicotine in wet AMD one step further, it may be that nicotinic receptors (which are also present in nonsmokers) may be a viable target for therapy.


Dr. Suñer is an associate professor of ophthalmology on the Retina Ser­vice at Duke University Eye Center and chief of ophthalmology, Durham Veterans Affairs Medical Center, Dur­­ham, N.C. Contact him at Duke Uni­versity Eye Center, DUMC 3802 Erwin Road, Durham, N.C. 27710, 919-6868-1876 (office), 919-681-6474 (fax), or ivan.suner@duke.edu.

Dr. Cousins is a professor of ophthalmology and director of the Duke Center for Macular Diseases, Duke Uni­versity Eye Center, Durham, NC. Contact him at Duke University Eye Center, DUMC 3802 Erwin Road, Durham, NC 27710, 919-684-3090 (office), 919-681-6474 (fax), or scott.cousins@duke.edu.


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