Emphysema And Vitamin A

An alternative hypothesis for the development of cigarette smoke-induced emphysema attributes the disease to consequences of vitamin A deficiency. There is evidence that suggests that cigarette smoke induces vitamin A deficiency and that this deficiency leads to emphysema. Support for this hypothesis is based on a series of related experiments. Weanling rats fed a vitamin A-deficient diet for 6 weeks with no smoke exposure develop emphysema (Baybutt et al., 2000). These pathological effects of vitamin A deficiency did not appear to be due to malnutrition because there was no difference in the average food intake or average body weight between rats fed the vitamin A-deficient diet and those fed the vitamin A-adequate diet for the length of this study. These results suggest that vitamin A deficiency per se creates emphy-semic lungs with the histological data presented in Fig. 1. Another novel and interesting result from this study was that within the same lung of the vitamin A-deficient rat, there were areas of inflammation along with areas of emphysema. It is likely that the areas of inflammation precede and eventually become the areas of emphysema.

The development of emphysema observed in the lungs of vitamin A-deficient rats is consistent with other studies. In an elastase-induced model of emphysema in rats, Massaro and Massaro (1996, 1997) found that development of emphysema could be prevented and to some extent reversed by the administration of all- trans RA. They also have shown an important role for RA in alveolar formation during development (Massaro and Massaro, 2001). RA initiates septation or formation of smaller and more numerous gas-exchange saccules or alveoli and increases the total number of alveoli relative to untreated rats (Massaro and Massaro, 2000). These studies suggest that vitamin A plays a critical role in lung development, maintenance of lung epithelium, and likely prevention or possible treatment of emphysema.

F. CIGARETTE SMOKING, VITAMIN A DEFICIENCY, AND THE DEVELOPMENT OF EMPHYSEMA

The overwhelming majority of cases of emphysema have been linked to cigarette smoking. Because vitamin A deficiency induces emphysema (Baybutt et al., 2000), the emphysema resulting from cigarette smoke could be the consequence of a localized vitamin A deficiency of the lungs. In support of this hypothesis, there is evidence that cigarette smoking leads to vitamin A deficiency. Edes and Gysbers (1993) reported that feeding rats benzopyrene, a constituent in cigarette smoke, depleted the vitamin A content of the lungs and liver. As previously noted, vitamin A-deficient lungs produce areas of emphysema (Baybutt et al., 2000). Therefore, the emphysema incurred from cigarette smoke could be the consequence of a localized vitamin A deficiency in the lungs. Further support for this hypothesis is reported in a study by

FIGURE 1. Vitamin A deficiency induces emphysema and lung inflammation. Representative section of the lung (A) of a rat receiving a diet with an adequate intake of vitamin A, and different areas from the lung of a rat fed a vitamin A-deficient diet (B and C). (A) shows a normal appearance, and (B) shows emphysematous areas of dilation of many alveolar spaces, extensive destruction of the septal walls, and thinning of the walls in other areas. Within the same lungs at different locations were areas of interstitial pneumonia (C), with distortion and/or reduction of the alveolar spaces. Small bronchi show presence of necrotic material and inflammatory cells in their lumen with partial disepithelization. Staining: H&E Magnification: 100x Bar (lower left corner) = 100 mm. Adapted from Baybutt et al. (2000).

FIGURE 1. Vitamin A deficiency induces emphysema and lung inflammation. Representative section of the lung (A) of a rat receiving a diet with an adequate intake of vitamin A, and different areas from the lung of a rat fed a vitamin A-deficient diet (B and C). (A) shows a normal appearance, and (B) shows emphysematous areas of dilation of many alveolar spaces, extensive destruction of the septal walls, and thinning of the walls in other areas. Within the same lungs at different locations were areas of interstitial pneumonia (C), with distortion and/or reduction of the alveolar spaces. Small bronchi show presence of necrotic material and inflammatory cells in their lumen with partial disepithelization. Staining: H&E Magnification: 100x Bar (lower left corner) = 100 mm. Adapted from Baybutt et al. (2000).

Li et al. (2003) in which rats were exposed to cigarette smoke from 20 nonfiltered commercial cigarettes/day in a smoke chamber for 5 days/week while the control group was exposed to air. After 6 weeks, vitamin A levels significantly decreased in the serum, lung, and liver of smoke-treated rats and produced areas of emphysema in the deficient rats (Fig. 2). It is interesting to note the similarities of the lung pathologies between the vitamin A-deficient lungs caused by a deficient diet and the vitamin A-deficient lungs caused by cigarette smoke. Both conditions produced lungs with areas of inflammation and areas of emphysema (compare Figs. 1 and 2).

There also appears to be a connection between poor vitamin A status and emphysema. For smoke-induced emphysema, the degree of emphysema is inversely related to the vitamin A content of the lung (Li et al., 2003). This study provided the first evidence that cigarette smoke inhalation by rats decreases lung and liver retinol levels, for there was no significant difference in mean daily food intake. Therefore, the depletion appeared to be largely attributed to the cigarette smoke. Others have found that intraperitoneal administration of tobacco extract or a tobacco constituent N'-nitrosonornicotine decreased the hepatic pool of vitamin A (Ammigan et al., 1990). When adult ferrets are exposed to cigarette smoke, retinoid catabolism increases, with the result of significantly lower levels of RA in the lung (Liu et al., 2000; Wang et al., 1999); however, lung retinol concentrations are not significantly altered in this study. This apparent discrepancy can be explained by the age of the animal. The adult ferret used in this study would have ample supply of vitamin A or retinol stored, which could prevent the adult ferret from becoming vitamin A deficient.

It should be noted that vitamin A deficiency-induced emphysema was observed in growing rats (Baybutt et al., 2000) when the development of the lung was still occurring. Whether the induction of vitamin A deficiency occurs in the adult animal or in humans in response to cigarette smoke remains to be determined. The precise role of vitamin A in smoke-induced emphysema is not known.

The amount of smoke exposure may be another important determinant for the smoke-induced vitamin A depletion. When weanling guinea pigs were exposed to a low dose of six cigarettes per day for 6 weeks, the levels of retinol in the lung increased (Mukherjee et al., 1995). In contrast, when weanling rats were exposed to a higher dose of 20 cigarettes per day, lung retinol decreased after 6 weeks.

The effects of cigarette smoke on vitamin A status in humans is less clear and more difficult to determine. Results from cross-sectional studies indicated an inverse relationship between plasma retinol and degree of airway obstruction (Morabia et al., 1990; Paiva et al., 1996). Some studies with smoking pregnant women have reported decreased serum levels of retinol (Chelchowska et al., 2001; Laskowska-Klita et al., 1999); while in other studies, cigarette smoking did not affect serum retinol levels

FIGURE 2. Cigarette smoke induces inflammation and emphysema. (A) Representative histological section of the lung of a control rat. No abnormalities were found. (B) Representative section of an area in the lung of a rat in response to cigarette smoke exposure for 6 weeks. The alveolar septa were significantly thickened with infiltration of inflammatory cells. Diffuse interstitial pneumonia was present. Large number of red blood cells are spread in the septa and the alveolar lumen. (C) Histological section of another area of the lung of the same cigarette smoke-exposed rat depicted in Fig. 2B. The alveolar wall was thinner than normal. Emphysematous area of dilation of many alveolar spaces, destruction of the septa wall was evident. Red blood cell and few chronic inflammatory cells were also present. Staining: Trichrome; Magnification: 400 x. Adapted from Li et al. (2003).

FIGURE 2. Cigarette smoke induces inflammation and emphysema. (A) Representative histological section of the lung of a control rat. No abnormalities were found. (B) Representative section of an area in the lung of a rat in response to cigarette smoke exposure for 6 weeks. The alveolar septa were significantly thickened with infiltration of inflammatory cells. Diffuse interstitial pneumonia was present. Large number of red blood cells are spread in the septa and the alveolar lumen. (C) Histological section of another area of the lung of the same cigarette smoke-exposed rat depicted in Fig. 2B. The alveolar wall was thinner than normal. Emphysematous area of dilation of many alveolar spaces, destruction of the septa wall was evident. Red blood cell and few chronic inflammatory cells were also present. Staining: Trichrome; Magnification: 400 x. Adapted from Li et al. (2003).

(al Senaidy et al., 1997; Lim et al., 2001), or even increased serum retinol levels (Pamuk et al., 1994). It is important to note that serum retinol is not an accurate measure for vitamin A status because most of this vitamin is stored in the liver. Methods have been developed for determining body content of vitamin A in humans using the dilution of an injected deuterated retinol (Furr et al., 1989; Haskell et al., 1997). Such methods have not been used for smokers and may help define the relationship between cigarette smokers and vitamin A status.

The mechanism for the cigarette smoke-induced vitamin A depletion and/ or impaired function of vitamin A is not known. It may be due to induction of the cytochrome P450 system. Exposure to cigarette smoke increases lung and liver cytochrome P450 isoforms CYP1A1 and CYP1A2 (Liu et al., 2003; Villard et al., 1988), which increases catabolism of RA (Liu et al., 2003; McSorley and Daly, 2000) and may lead to vitamin A depletion. Another mechanism for the cigarette smoke-induced vitamin A depletion may be that the cigarette smoke constituents block cellular uptake of retinol and create a functional deficiency. The cigarette smoke constituent benzopyrene inhibits uptake of retinol by tracheal cells and therefore could block its function (Biesalski and Engel, 1996).

G. EMPHYSEMA, VITAMIN A, AND ELASTIN METABOLISM

Another characteristic of emphysema is a decreased elastic recoil after exhalation because of a decrease in the amount of the matrix protein elastin, which provides structural framework and elasticity for the lung. There is less elastin staining detected in the lungs of vitamin A-deficient rats (Baybutt et al., 2000). Furthermore, cigarette smoking that has been found to induce vitamin A deficiency (Li et al., 2003) impairs elastin synthesis in the lungs of hamsters in an elastase-induced emphysema model (Osman et al., 1985). Decreased elastin staining can also be observed in the lungs of rat fetuses from vitamin A-deficient mothers and is associated with a decreased elastin mRNA in the fetal lung (Antipatis et al., 1998). In contrast, the levels of RA, RA receptor, and cellular retinol-binding protein are highest in lung interstitial fibroblasts during the time of maximal elastin synthesis, when extensive enlargement of the alveolar surface area occurs (McGowan et al., 1995). Despite the uncertainty of the precise mechanism for elastin preservation, vitamin A maintains elastin levels in the lung.

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