Airway vasculature

Airway surfaces, like skin, are continually exposed to the ambient environment. In contrast to skin submucosal vessels, however, w hich shed excess heat by vasodilating when heated and conserve heat by vasoconstricting when chilled, it is unclear how the airway vasculature responds to temperature extremes. Inspiring cold air poses two challenges to conducting airway tissues the risk of tissue injury should inadequate heat reach the airway surface and excessive body heat loss due to increasing the radial temperature gradient. Vasodilation would protect airway tissue but increase heat loss, while vasoconstriction would produce the opposite effect. 

Widdicombe JG. The airway vasculature. Exp Physiol 1993 78 433-452. Djukanovic R, Wilson SJ, Howarth PH. Pathology of rhinitis and bronchial asthma. Chn Exp Ahergy 1996 26(suppl 3) 44-51. 

FIGURE 5.18 Vasculature structure along a portion of bronchia muscle. Airway epithelia are not shown in this figure but lie between the submucosal venules and the airway lumen. Modified from Deffe-bach et al. ... 

The most common etiology is exposure to environmental tobacco smoke, but other chronic inhalational exposures can also lead to COPD. Inhalation of noxious particles and gases stimulates the activation of neutrophils, macrophages, and CD8+ lymphocytes, which release a variety of chemical mediators, including tumor necrosis factor-a, interleukin-8, and leukotriene B4. These inflammatory cells and mediators lead to widespread destructive changes in the airways, pulmonary vasculature, and lung parenchyma. 

The direction of arterial blood flow in the nose runs anteriorly against inspiration. Blood vessels are arranged in such a manner as to provide an erectile capacity to the mucosa enabling the airway to widen and narrow. Blood flow through the autonomically controlled vasculature of the nasal tissue is of importance in the conditioning of inspired air. 

Preliminary studies in animals suggest that airway smooth muscle, like that in the vasculature, is effectively relaxed by nitric oxide. This very lipophilic drug can be inhaled as a gas in acute asthma and dilates the pulmonary blood vessels as well as the airway smooth muscle. Although nitric oxide itself—or nitric oxide donors—may prove of value in acute severe asthma, it appears likely that they will be more useful in pulmonary hypertension (for which nitric oxide is already approved). 

The nasal mucosa is highly vascular superficial and deep layers of arterioles supply the lamina propria and between the venules and capillaries there are numerous sinuses or venous lakes which are linked to erectile tissue, particularly in the middle and inferior turbinates, which enable the airways to widen or narrow. This autonomically controlled vasculature of the nasal tissue, in combination with its rich supply of secretory cells, is of importance in the modification of inspired air. 

Within the benzopyran series, analogues that have relative selectivity for the vasculature compared with the airways have been relatively easy to discover, for example the tetrahydronaphthalene (49) which has an IC50 of 4.5 /iM against K elevated tone in GPPV, but does not attain an IC50 against spontaneous tone in OPTS. This compound (49) possesses antihypertensive activity in vivo in the SHR [88]. 

Whether this can explain the mechanism of the selectivity seen with BRL 55834 (32) and rimakalim (33) remains to be proved. Certainly, the studies which have been reported using smooth muscle cells from the portal vein need to be extended to airways smooth muscle. This is particularly important for BRL 55834 (32) which has been reported to activate two K channels in bovine airways smooth muscle and shows selectivity for the airways relative to levcromakalim (2). Similarly, it will be interesting to ascertain whether the selectivity for the vasculature found with compounds... 

The reason why KCAs can be selective for the vasculature with little effect on the airways requires further study, but an influence on a different channel cannot be ruled out. For example, in GPTS, extracellular rubidium has the effect of blocking the cromakalim-stimulated and Rb" ... 

In the first, the known series of KCAs continues to be modified, so that compounds, such as BRL 55834 (32), have emerged that have a relative selectivity for the airways over the vasculature, possibly by the modulation of channels that are not opened by the more conventional members of the class. In the second, novel structures such as the henzimidazolone (44) that open different channels in different tissues are reported. In the third approach, compounds such as LP-805 (42) and SCA40 (43) have been discovered that have additional pharmacological actions, that together with channel modulation, are potentially advantageous for the treatment of certain disease states. 

The increase in vascular permeability associated with inflammation often is accompanied by the emigration of leukocytes out of the micro vasculature. Neutrophils and eosinophils are found in the airways of guinea-pigs, rabbits, dogs and humans after allergen challenge they are also in the airway mucosa of patients who have died from asthma (Williams et al., 1991). What then is the relationship between vascular permeability and neutrophil migration ... 

One isofomi is induced in response to proinflammatory cytokines, inducible NO synthase (iNOS), in airway epithelial ceUs and inflammatory cells of asthmatic airways. NO produces smooth muscle relaxation in the vasculature and bronchials however, it appears to amplify the inflammatory process and is unlikely to be of therapeutic benefit. Recent investigations measuring exhaled NO concentrations have suggested that it may be a useful measure of ongoing lower airways inflammation in patients with asthma and for measuring effectiveness of therapy. ... 

The respiratory system consists of the lungs, conducting airways, pulmonary vasculature, respiratory muscles, and surrounding tissues and structures (Figure 7.1). Each plays an important role in influencing... 

Napel S, Bergin C, Paranjpe D, Rubin GD (1992) Maximum and minimum intensity projection of spiral CT data for simultaneous 3D imaging of the pulmonary vasculature and airways (abstract). 78th 52 Scientific Sessions Radiological Society of North America Bd. 185(p). Chicago Radiology 126... 

The physiological and pharmacological effects of histamine are mediated through four different receptors Hi, Hj, Hj, and Ht, all members of the 7-transmembrane g protein-coupled receptor (GPCR) family with amino terminal glycosylation sites and phosphorylation sites for protein kinases A and C. The receptors are widely expressed on different tissues that are responsive to histamine. For the Hi receptor these tissues include smooth muscle cells of the airways and vasculature, the gastrointestinal tract, cardiovascular system, neutrophils, endothelial cells, T and B cells, hepatocy tes, nerve... 

Major and minor sites of action the major sites of action include the HI and H2 receptors, which are widely expressed throughout the body. The HI receptors are expressed in neurons, smooth muscle of airways, and vasculature, while H2 receptors are primarily expressed in gastric mucosa parietal cells, smooth muscle, and cardiac cells. Although H3 and H4 receptors have been discovered in histaminergic neurons and bone marrow, respectively, currently there are no inverse agonists available for clinical use. 

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