Airways, plasma leakage

Assessment of Plasma Leakage in Airways of Animals and Humans... 

There are several consequences of an increase in the permeability of the blood vessels of the airway mucosa. Plasma leakage could result in mucosal edema and the movement of fluid into the airway lumen, both of which could contribute to airflow obstruction. In addition, plasma-derived inflammatory mediators could form in the mucosa and airway lumen, and extravasated plasma proteins could increase the viscosity of sputum. 

Whether an increase in vascular permeability results in mucosal edema depends on the balance between the amount of leakage into the mucosa and the rate of clearance from the mucosa, either through the lymphatics or across the epithelium into the airway lumen. The increase of vascular permeability produced by inflammatory stimuli can result in the bulk flow of plasma into the airway mucosa (Renkin, 1992). The amount of plasma leakage depends upon the number of gaps that form in the endothelium of the leaky vessels, the duration of the gaps and the intravascular pressure that drives the extravasation (Clough, 1991 Taylor and Ballard, 1992). The movement of plasma proteins and other osmotically active solutes into the mucosa can increase the interstitial oncotic pressure, which favors the net movement of fluid out of vessels and further increases the amount of leakage (Taylor and Ballard, 1992). 

The effect of plasma leakage on airway resistance depends on the amount of mechanical obstruction caused by the increase in mucosal thickness, accumulation of intraluminal fluid and possible reflex bronchocon-striction. In addition, the impact on airway conductance depends on where in the tracheobronchial tree the fluid accumulates. Theoretical models predict that increased mucosal wall thickness itself may have little effect on airflow, but it could exa erate the luminal narrowing caused by bronchoconstriction (James etal., 1989 Wiggs et al., 1990 Yager et ai., 1991). Although this effect probably would be negligible in the trachea and large bronchi, it could be important in peripheral airways. 

Several mediators have been implicated in the plasma leakage associated with airway inflammation. Most of these mediators have relatively transient effects on vascular permeabUity, because of the existence of mechanisms that limit the duration of their effects. For example, the action of substance P on vascular endothelial ceUs is Umited by the phosphorylation and internalization of neurokinin (Nki) receptors (Bowden et al., 1994a) and by the degradation of substance P by neutral endopeptidase and other enzymes (Umeno et al., 1989 Nadel, 1992 Katayama etal., 1993). 

As discussed in Section 3.3, few histopathological studies of asthma have focused specifically on the microvasculature. Nonetheless, there is evidence that neovascularization is one of the changes in the airways of asthmatics (Kuwano et al., 1991). This observation in potentially important because newly formed blood vessels may be abnormally leaky (Schoefl, 1967) or abnormally responsive to inflammatory mediators (McDonald, 1992). The plasma leakage that occurs in the airway mucosa of asthmatics could result from the heightened response of the mucosal blood vessels to inflammatory mediators. 

Depletion of endogenous glucocorticoids in experimental animals can increase the amount of plasma leakage produced by allergen challenge and other inflammatory stimuli (Boschetto et al., 1992 Ohrui et al., 1992). This observation may be important clinically, because the responsiveness of airway blood vessels to inflammatory mediators could increase after glucocorticoid treatment is stopped. 

Selective 182-adrenergic receptor agonists (ft agonists) are widely used in the treatment of airway diseases such as asthma because of their bronchodilating action. In addition, ft agonists have anti-inflammatory effects, in that they can inhibit the release of inflammatory mediators and can decrease plasma leakage (Svensjo et al., 1977 Tomioka etal., 1981 Erjefalt and Persson, 1986 Barnes,... 

Nedocromil, which is structurally different from cromoglycate, also has multiple anti-inflammatory actions (Barnes, 1993c). For example, nedocromil can decrease allergen-induced plasma leakage in guinea-pig airways (Evans et al., 1988b). This effect probably involves the inhibition of mediator release (Moqbel eta.1., 1988). However, an action on vascular endothelial cells... 

Several reports suggest that peptides released from nerve fibers in the airways can decrease the plasma leakage produced by inflammatory mediators (Raud, 1993). For example, calcitonin gene-related peptide (CGRP), which usually co-exists with substance P in sensory nerve fibers, may have an anti-edema effect in the airways (Raud etal.. 

Nedocromil inhibits the development of early and late bronchoconstriction responses to inhaled antigen. The development of airway hyperresponsiveness to nonspecific bronchoconstrictors was also inhibited in airway microvasculature leakage. Nedocromil is bound to plasma proteins to the extent of 89%, is not metabolized, and is excreted unchanged. 

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