Prevention of Cigarette Smoke Induced Microvascular Dysfunction

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Based on the knowledge that we have gained of the path-omechanism of cigarette smoke-induced microvascular dysfunction, we must acknowledge that while some effects may be due to nicotine, many other effects are due to the reactive oxygen species that are either introduced into the organism by the smoke per se, or else released from activated neutrophils, primarily in the lungs of smokers—in response to cigarette smoke inhalation. Based on our initial finding that cigarette smoke-induced microcirculatory dysfunction was effectively counteracted by superoxide dismu-tase, we tried to inhibit the generation of reactive oxygen species in the organism of a smoke-exposed animal with the antioxidants vitamin C (which acts as water-soluble antioxidant to prevent the initiation of lipid peroxidation) or vitamin E (which is lipid-soluble and acts as a chain-breaking antioxidant). When the animals were then exposed to cigarette smoke, we found that microcirculatory dysfunction was almost entirely prevented in vitamin C-treated animals, whereas no such inhibitory effect was seen with vitamin E [4]. In further studies we could demonstrate that vitamin C acted by preventing the formation of platelet activating factor-like lipids in the hamster blood and that these lipids accounted for most of the microcirculatory dysfunction secondary to cigarette smoke exposure [5]. In the past few years, our studies on the inhibitory action of vitamin C have been reproduced and translated into the human situation: Several authors have independently demonstrated that oral or parenteral application of vitamin C to human subjects restores cigarette smoke-induced endothelial dependent vasoregulatory dysfunction in the calf, the forearm, and the nailfold microcirculation. It remains to be seen whether these interventions will eventually reduce cigarette smoke-associated pathology.


Cigarette smoke: Cigarette smoke can be divided into two phases, gas-phase smoke and tar (which gets trapped in filter pores). Tar contains high concentrations of radicals, which are sufficiently stable to be detectable by electron spin resonance. Many of the components of cigarette tar are water soluble; hence, aqueous extracts of cigarette tar reduce oxygen to form activated oxygen species that can cause biological damage. In contrast, the radicals in the gas phase are very short-lived, yet entertain a remarkable steady state, yielding high concentrations even in "aged" smoke. Many of these radicals enter the lungs of smokers and avidly interact with biological matter, as becomes manifest in the rapid inactivation of a-1 proteinase inhibitor—a key mechanism of cigarette smoke-induced emphysema formation.

PAF-like lipids: Platelet-activating factor (PAF) is a potent proinflam-matory phospholipid with diverse pathological and physiological effects. This bioactive phospholipid mediates processes as diverse as wound healing, inflammation, ischemia-reperfusion injury, angiogenesis, and reproduction. As first described by a team of researchers at the University of Utah, the unregulated production of structural analogs of PAF by nonspecific oxidative reactions has expanded the superfamily of signaling molecules to include "PAF-like" lipids whose mode of action is identical to that of authentic PAF. Inappropriate activation of this signaling pathway is associated with many diseases in which inflammation is thought to be one of the underlying features.

Vitamin C: Vitamin C is a water-soluble vitamin that is necessary for normal growth and development. It is required in the synthesis of collagen in connective tissue, neurotransmitters, steroid hormones, carnitine, and the conversion of cholesterol to bile acids, and it enhances iron bioavailability. Vitamin C plays a paramount role as an antioxidant and free radical scavenger and helps protect the body against the aggressive action of reactive oxygen species.


1. Lehr, H. A. (2000). Microcirculatory dysfunction induced by cigarette smoking. Microcirculation 7, 367-384.

3. Asano, M., and Branemark, P. I. (1970). Cardiovascular and microvascular responses to smoking in man. Adv. Microcirc. 3, 152-158. This article is outstanding in the field of microcirculation research, being the first study of the human microcirculation by intravital microscopy using an implanted observation chamber. Implantation of the observation chamber was performed in the delicate, rather loose skin in the thoracic aspect of the upper arm in volunteers. Using this model, Asano could demonstrate for the first time significant changes in blood flow through microvessels in human volunteers during cigarette smoke exposure.

4. Lehr, H. A., Frei, B., and Arfors, K. E. (1994). Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothe-lium in vivo. Proc. Natl. Acad. Sci. USA 91, 7688-7692. Lehr and coworkers described in a paper in Free Radical Biology & Medicine for the first time the effect of cigarette smoke on the microcirculation, involving the generation and action of superoxide dismutase. In the PNAS paper from 1994, feeding hamsters for 1 week with a vitamin C—supplemented diet entirely prevented cigarette smoke—induced leukocyte adhesion in postcapillary venules. No such beneficial effect was seen for the lipid-soluble antioxidant vitamin E. As explanation for these observations, the authors proposed that vitamin C scavenges oxidant species that enter the bloodstream through the cigarette smoke and hence prevents their action in the microcirculation (see Ref. [5]).

5. Lehr, H. A., Weyrich, A. S., Jurek, A., Saetzler, R. K., Arfors, K. E., Zimmermann, G. A., Prescott, S. M., Mclntyre, T. M. (1997). Vitamin C blocks antiinflammatory platelet-activating factor like lipids created by cigarette smoking. J. Clin. Invest. 99, 2358-2364. Based on the landmark observation of PAF-like lipids (PAF-LL) by the group of Tom McIntyre and coworkers that are generated by the attack of reactive oxygen species on phospholipids, Lehr and coworkers went on to study whether the inhibitory effects on vitamin C in their smoking hamster model was linked to the formation of PAF-LL in the bloodstream and their inhibition by vitamin C. The two groups teamed up to demonstrate that indeed cigarette smoke exposure generates in the bloodstream of smoke-exposed hamsters the formation of a factor that elicits leukocyte adhesion and leukocyte—platelet aggregation through a mechanism that is both dependent on the PAF receptor and inhibited by vitamin C. The demonstration that the smoke induced adhesive action was blocked by PAF receptors in vitro and in vivo alike suggests that indeed PAF-LL are formed in an intact animal organism in response to free radical attack.

6. Lehr, H. A., and Arfors, K. E. (1994). Mechanisms of tissue damage by leukocytes. Curr. Opin. Hematol. 1, 92-99.

7. Drost, E. M., Selby, C., Bridgeman, M. M., and MacNee, W. (1993). Decreased leukocyte deformability after acute cigarette smoking in humans. Am. Rev. Respir. Dis. 148, 1277-1283.

Capsule Biography

Dr. Hans-Anton Lehr has been involved for almost 15 years in microcirculation research, predominantly by intravital fluorescence microscopy using the dorsal skinfold chamber model in hamsters and mice. His studies have focused on questions of ischemia-reperfusion injury, atherogenesis, cigarette smoke-induced microcirculatory dysfunction, and, lately, tumor angiogenesis. Dr. Lehr is a diagnostic pathologist currently acting as Professor of Pathology at the University of Mainz Medical Center, Germany.

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