2. Respiratory diseases and cerebral vascular endothelial dysfunction

According to modern conceptions, the central nervous system is an important participant in the pathogenesis of a number of chronic respiratory diseases, including those having a nicotineassociated nature. An important regulator of hemoperfusion of the brain is the vascular endothelium [8]. There are specific endothelium-dependent reactions in the arteries of the brain [9, 15]. Cerebral autoregulation maintains constant blood flow (CBF) through the brain in spite of changing mean arterial pressure. Autoregulation of cerebral blood flow consists of mechanoand chemoregulation. Chemoregulation is in direct correlation to the serum level of carbon dioxide and is, contrary to mechanoregulation, independent of changes in mean arterial pressure.

Mechanoregulation depends on transmural pressure gradient and endothelial vasodilatation. Mechanoregulation has been shown to be the main supervisory mechanism of CBF. However, it is well established that endothelial vasodilatation of greater arteries is much more pronounced in cerebral vasculature than elsewhere. Proper endothelial function is of crucial importance in regulation in many vascular beds. Dysfunctional cerebral endothelium releases less endothelial NO. As a consequence, relaxation of smooth muscle cells of small arteries is disturbed. Studies in animals and humans have revealed that mechanoregulation is not compromised even in older age and pathological conditions harming endothelium. On the contrary, outcomes of many studies and clinical reports confirm the dependency of chemoregulation of CBF on vascular endothelial integrity. Reduced chemoregulation was found in patients with dysfunctional cerebral endothelium [9]. The development of cognitive disorders recognized by experts as a typical systemic manifestation of the disease remains insufficiently investigated so far in the pathogenesis of nicotine-associated respiratory diseases and in particular COPD [10, 11, 16, 17]. It has been proven that one of the manifestations of vascular dysfunction can be a violation of the regional correspondence of the blood flow, which has a significant effect on the further course of the disease [12, 13, 18, 19]. According to research, a complex cascade of teratogenesis in respiratory diseases initiates acute and chronic hypoxemia and, in severe cases, hypercapnia. In turn, cerebral dysfunction in COPD can be a factor in the violation of respiratory and vasomotor reactivity in response to hypercapnia due to a decrease in the sensitivity of central chemoreceptors to it. It is known that central chemoreceptors represent up to 80% of the total chemo-sensitivity of the organism to carbon dioxide [4, 5]. The consequence of the violation of central vasomotor control is inadequate blood supply to various areas, including the brain itself [4, 5, 15]. Not being invalidating, violations of the central nervous system significantly affect the ability to work and social activity of patients. The main consequence of the violation of brain perfusion in these patients is the violation of the integral function of the central nervous system, which results in inadequate blood supply to various areas, including the brain [5, 7, 9]. This becomes the closing link of a peculiar "vicious circle" of regional vascular dysfunctions. Figure 2 shows the place and role of functional imbalance of endothelium-dependent mechanisms in the pathogenesis of respiratory diseases.

#### 2.1. Effect of tobacco smoke components on vascular function

Consequences and mechanisms of tobacco combustion products damaging vascular bed still require more research. Tobacco smoking is known to cause ED [19, 21] that has its peculiarities depending on the intensity and time of exposure as well as characteristics of the arteries. For instance, one of the crucial characteristics of cerebral blood circulation is a high level of autonomous self-regulation providing relative independence of cerebral hemodynamics from shifts in systemic circulation. Short-term exposure to tobacco smoke results in damage from its toxins on vascular endothelium and activation of sympathoadrenal system. [22]. Chronic exposure to tobacco smoke leads to a lower level of endothelial NO synthase (eNOS) activity and NO synthesis, adhesion molecules expression on the surface of endothelial cells, protein kinase C (PKC) activation and intensification of lipid peroxidation followed by persistent remodeling of the vascular wall [23, 24]. Some experiments describe development of endothelial dysfunction of cerebral and conductance arteries in mice exposed to tobacco smoke that was characterized by significant intensification and predominance of constricting activity of arteries, as well as abnormal reduction of cerebral arterial vasodilatory reserve along with asymmetric increase of carotid artery constriction [11, 14]. Apart from endothelial dysfunction and alterations of vasomotor reactions in response to tobacco smoking, some experiments revealed a connection between long-term exposure to tobacco smoke and irreversible changes in large arteries, such as wall thickening and deterioration of their mechanical properties [24, 25]. At the same time, smoke-exposed rats showed elevated levels of elastase and progressing degenerative changes of thoracic and abdominal aorta accompanied by a lower quality of their elastic and mechanical properties [26]. Some researches show that smoking increases risk of development of abdominal aortic aneurysm (AAA). For example, AAA growth rate was lower in those with low ankle/brachial pressure index and diabetes but higher for current smokers. No other factor (including lipids and blood pressure) was associated with AAA growth. [27]. Current smokers were 7.6 times more likely to have an AAA than non-smokers. Ex-smokers were 3.0 times more likely to have an AAA than non-smokers. Duration of smoking was significantly associated with an increased risk of AAA, and there was a clear linear dose response relationship with the duration of smoking; each year of smoking increased the relative risk of AAA by 4% [28].

Smoking, Respiratory Diseases and Endothelial Dysfunction

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Figure 2. Functional processes imbalance due to endothelial dysfunction in respiratory diseases.

Smoking, Respiratory Diseases and Endothelial Dysfunction http://dx.doi.org/10.5772/intechopen.73555 311

Figure 2. Functional processes imbalance due to endothelial dysfunction in respiratory diseases.

Mechanoregulation depends on transmural pressure gradient and endothelial vasodilatation. Mechanoregulation has been shown to be the main supervisory mechanism of CBF. However, it is well established that endothelial vasodilatation of greater arteries is much more pronounced in cerebral vasculature than elsewhere. Proper endothelial function is of crucial importance in regulation in many vascular beds. Dysfunctional cerebral endothelium releases less endothelial NO. As a consequence, relaxation of smooth muscle cells of small arteries is disturbed. Studies in animals and humans have revealed that mechanoregulation is not compromised even in older age and pathological conditions harming endothelium. On the contrary, outcomes of many studies and clinical reports confirm the dependency of chemoregulation of CBF on vascular endothelial integrity. Reduced chemoregulation was found in patients with dysfunctional cerebral endothelium [9]. The development of cognitive disorders recognized by experts as a typical systemic manifestation of the disease remains insufficiently investigated so far in the pathogenesis of nicotine-associated respiratory diseases and in particular COPD [10, 11, 16, 17]. It has been proven that one of the manifestations of vascular dysfunction can be a violation of the regional correspondence of the blood flow, which has a significant effect on the further course of the disease [12, 13, 18, 19]. According to research, a complex cascade of teratogenesis in respiratory diseases initiates acute and chronic hypoxemia and, in severe cases, hypercapnia. In turn, cerebral dysfunction in COPD can be a factor in the violation of respiratory and vasomotor reactivity in response to hypercapnia due to a decrease in the sensitivity of central chemoreceptors to it. It is known that central chemoreceptors represent up to 80% of the total chemo-sensitivity of the organism to carbon dioxide [4, 5]. The consequence of the violation of central vasomotor control is inadequate blood supply to various areas, including the brain itself [4, 5, 15]. Not being invalidating, violations of the central nervous system significantly affect the ability to work and social activity of patients. The main consequence of the violation of brain perfusion in these patients is the violation of the integral function of the central nervous system, which results in inadequate blood supply to various areas, including the brain [5, 7, 9]. This becomes the closing link of a peculiar "vicious circle" of regional vascular dysfunctions. Figure 2 shows the place and role of functional imbalance of endothelium-dependent mechanisms in the pathogenesis of

310 Endothelial Dysfunction - Old Concepts and New Challenges

respiratory diseases.

2.1. Effect of tobacco smoke components on vascular function

Consequences and mechanisms of tobacco combustion products damaging vascular bed still require more research. Tobacco smoking is known to cause ED [19, 21] that has its peculiarities depending on the intensity and time of exposure as well as characteristics of the arteries. For instance, one of the crucial characteristics of cerebral blood circulation is a high level of autonomous self-regulation providing relative independence of cerebral hemodynamics from shifts in systemic circulation. Short-term exposure to tobacco smoke results in damage from its toxins on vascular endothelium and activation of sympathoadrenal system. [22]. Chronic exposure to tobacco smoke leads to a lower level of endothelial NO synthase (eNOS) activity and NO synthesis, adhesion molecules expression on the surface of endothelial cells, protein kinase C (PKC) activation and intensification of lipid peroxidation followed by persistent remodeling of the vascular wall [23, 24]. Some experiments describe development of endothelial dysfunction of cerebral and conductance arteries in mice exposed to tobacco smoke that was characterized by significant intensification and predominance of constricting activity of arteries, as well as abnormal reduction of cerebral arterial vasodilatory reserve along with asymmetric increase of carotid artery constriction [11, 14]. Apart from endothelial dysfunction and alterations of vasomotor reactions in response to tobacco smoking, some experiments revealed a connection between long-term exposure to tobacco smoke and irreversible changes in large arteries, such as wall thickening and deterioration of their mechanical properties [24, 25]. At the same time, smoke-exposed rats showed elevated levels of elastase and progressing degenerative changes of thoracic and abdominal aorta accompanied by a lower quality of their elastic and mechanical properties [26]. Some researches show that smoking increases risk of development of abdominal aortic aneurysm (AAA). For example, AAA growth rate was lower in those with low ankle/brachial pressure index and diabetes but higher for current smokers. No other factor (including lipids and blood pressure) was associated with AAA growth. [27]. Current smokers were 7.6 times more likely to have an AAA than non-smokers. Ex-smokers were 3.0 times more likely to have an AAA than non-smokers. Duration of smoking was significantly associated with an increased risk of AAA, and there was a clear linear dose response relationship with the duration of smoking; each year of smoking increased the relative risk of AAA by 4% [28].
