ROLE OF PLASMA EXUDATION IN ASTHMATIC AIRWAYS

doi:10.1016/S0140-6736(86)90533-7

The Lancet

Volume 328, Issue 8516, 15 November 1986, Pages 1126-1129

https://doi.org/10.1016/S0140-6736(86)90533-7 Get rights and content

Abstract

In normal airway defence and especially in asthma, mediators released from inflammatory cells will directly affect the walls of the abundant airway microvessels, making them much more permeable to macromolecules. Through large gaps between actively separated (contracted?) endothelial cells of venules of the tracheobronchial circulation, there is a bulk flow of proteinaceous plasma. The plasma exudate is distributed in the airway wall and it readily passes across an inflamed mucosa into the airway lumen. Plasma in the airway wall causes oedema, which may result in hyperresponsiveness and epithelial shedding. In the lumen its effects are formation of mucus plugs and inhibition of mucociliary transport, and its potent mediators such as the protein products of the kinin, complement, and clotting systems are released. Thus plasma exudation may operate in several aspects of asthmatic diathesis. By positive feedback mechanisms and recruitment and conditioning of inflammatory cells plasma exudate may amplify the inflammatory process.

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Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma
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An early demonstration of prompt challenge-induced microvascular-epithelial exudation in guinea pig tracheobronchial airways suggested that plasma macromolecules appeared on the mucosal surface independent of their charge and size.29 The indiscriminate microvascular-epithelial passage of macromolecules explains why the process is called exudation rather than transudation, the latter name emphasizing fluid movement.35-37 Thus different-sized plasma proteins have appeared on challenged but intact guinea pig and human airway mucosal surfaces in nearly the same concentration ratios as occur in circulating blood.24,29,31,38
This review discusses in vivo airway aspects of plasma exudation in relation to current views on epithelial permeability and epithelial regeneration in health and disease. Microvascular-epithelial exudation of bulk plasma proteins characteristically occurs in asthmatic patients, being especially pronounced in those with severe and exacerbating asthma. Healthy human and guinea pig airways challenged by noninjurious histamine-leukotriene–type autacoids also respond through prompt mucosal exudation of nonsieved plasma macromolecules. Contrary to current beliefs, epithelial permeability in the opposite direction (ie, absorption of inhaled molecules) has not been increased in patients with asthma and allergic rhinitis or in acutely exuding healthy airways. A slightly increased subepithelial hydrostatic pressure produces such unidirectional outward perviousness to macromolecules. Lack of increased absorption permeability in asthmatic patients can further be reconciled with occurrence of epithelial shedding, leaving small patches of denuded basement membrane. Counteracting escalating barrier breaks, plasma exudation promptly covers the denuded patches. Here it creates and sustains a biologically active barrier involving a neutrophil-rich, fibrin-fibronectin net. Furthermore, in the plasma-derived milieu, all epithelial cell types bordering the denuded patch dedifferentiate and migrate from all sides to cover the denuded basement membrane. However, this speedy epithelial regeneration can come at a cost. Guinea pig in vivo studies demonstrate that patches of epithelial denudation regeneration are exudation hot spots evoking asthma-like features, including recruitment/activation of granulocytes, proliferation of fibrocytes/smooth muscle cells, and basement membrane thickening. In conclusion, nonsieved plasma macromolecules can operate on the intact airway mucosa as potent components of first-line innate immunity responses. Exuded plasma also takes center stage in epithelial regeneration. When exaggerated, epithelial regeneration can contribute to the inception and development of asthma.
Brain natriuretic peptide: Much more than a biomarker
2016, International Journal of Cardiology
Citation Excerpt :
This discrepancy may be explained by the fact that BNP probably does not act as a direct bronchodilator on ASM [56]. In effect, it has been suggested that the ability of BNP to improve lung function in vivo may be related to other actions, such as the reduction of airways microvascular leakage and plasma exudation into the airways [79,80]. The bronchodilator effect of BNP has also been investigated in human small airways by using PCLS preparations and it has been compared with the effect elicited by PL-3994 [77].
Brain natriuretic peptide (BNP) modulates several biological processes by activating the natriuretic peptide receptor A (NPR-A). Atria and ventricles secrete BNP. BNP increases natriuresis, diuresis and vasodilatation, thus resulting in a decreased cardiac workload.
BNP and NT-proBNP, which is the biologically inactive N-terminal portion of its pro-hormone, are fast and sensitive biomarkers for diagnosing heart failure. The plasma concentrations of both BNP and NT-proBNP also correlate with left ventricular function in patients with acute exacerbation of COPD, even without history of heart failure. Several studies have been conducted in vitro and in vivo, both in animals and in humans, in order to assess the potential role of the NPR-A activation as a novel therapeutic approach for treating obstructive pulmonary disorders. Unfortunately, these studies have yielded conflicting results.
Nevertheless, further recent specific studies, performed in ex vivo models of asthma and COPD, have confirmed the bronchorelaxant effect of BNP and its protective role against bronchial hyperresponsiveness in human airways. These studies have also clarified the intimate mechanism of action of BNP, represented by an autocrine loop elicited by the activation of NPR-A, localized on bronchial epithelium, and the relaxant response of the surrounding ASM, which does not expresses NPR-A.
This review explores the teleological activities and paradoxical effects of BNP with regard to chronic obstructive respiratory disorders, and provides an excursus on the main scientific findings that explain why BNP should be considered much more than a biomarker.
Apelin attenuates UVB-induced edema and inflammation by promoting vessel function
2011, American Journal of Pathology
Citation Excerpt :
Acute photodamage of the skin is characterized by epidermal hyperplasia, erythema, and edema formation. Edema is caused by accumulation of extracellular fluid due to excess leakage from hyperpermeable blood vessels33 and by a failure of lymphatic vessels to sufficiently drain the fluid from the interstitium.12 Moreover, the dysfunction of lymphatic vessels also results in reduced clearance of macrophages from the tissue via lymphatic drainage,34 suggesting that the function of lymphatic vessels is profoundly related to the process of UVB-induced inflammation.
Apelin, the ligand of the G protein–coupled receptor APJ, is involved in the regulation of cardiovascular functions, fluid homeostasis, and vessel formation. Recent reports indicate that apelin secreted from endothelial cells mediates APJ regulation of blood vessel caliber size; however, the function of apelin in lymphatic vessels is unclear. Here we report that APJ was expressed by human lymphatic endothelial cells and that apelin induced migration and cord formation of lymphatic endothelial cells dose-dependently in vitro. Furthermore, permeability assays demonstrated that apelin stabilizes lymphatic endothelial cells. In vivo, transgenic mice harboring apelin under the control of keratin 14 (K14-apelin) exhibited attenuated UVB-induced edema and a decreased number of CD11b-positive macrophages. Moreover, activation of apelin/APJ signaling inhibited UVB-induced enlargement of lymphatic and blood vessels. Finally, K14-apelin mice blocked the hyperpermeability of lymphatic vessels in inflamed skin. These results indicate that apelin plays a functional role in the stabilization of lymphatic vessels in inflamed tissues and that apelin might be a suitable target for prevention of UVB-induced inflammation.
The effect of airway remodelling on airway hyper-responsiveness in asthma
2011, Respiratory Medicine
Citation Excerpt :
However, the improvement in airway distensibility, which was of borderline significance, suggests that airway distensibility, measured by FOT, is partly influenced by steroid-responsive inflammation. The precise mechanism of this is unclear but it is likely that the steroid-responsive components of inflammation, including oedema and plasma exudate resulting from microvascular leakage,31,32 thicken the airway walls thereby reducing airway distensibility. This is supported by the results of imaging studies in which wall thickness decreases with ICS.19
The mechanisms of airway hyper-responsiveness are only partially understood and the contribution of airway remodelling is unknown. Airway remodelling can be assessed by measuring airway distensibility, which is reduced in asthma, even when lung function is normal. We hypothesised that airway remodelling contributes to airway hyper-responsiveness in asthma, independent of steroid-responsive airway inflammation.
To determine the relationship between airway distensibility and airway responsiveness at baseline and after 12 weeks of inhaled corticosteroid therapy in a group of asthmatics with airway hyper-responsiveness.
Nineteen doctor-diagnosed asthmatics had airway distensibility measured as the slope of the relationship between conductance and lung volume by the forced oscillation technique. Lung function, exhaled nitric oxide and methacholine challenge were also measured. Subjects had inhaled corticosteroid therapy for 12 weeks after which all measurements were repeated.
At baseline, airway distensibility (mean, 95%CI) was 0.19(0.14–0.23) cm H₂O⁻¹ s⁻¹, exhaled nitric oxide was 13.1(10.3–16.6) ppb and airway distensibility correlated with eNO (p = 0.04) and disease duration (p = 0.02) but not with airway responsiveness (p = 0.46), FEV₁ (p = 0.09) or age (p = 0.23). After treatment, exhaled nitric oxide decreased (p = 0.0002), FEV₁ improved (p = 0.0001), airway responsiveness improved (p = 0.0002), and there was a small improvement in airway distensibility but it did not normalise (p = 0.05). Airway distensibility was not correlated with either exhaled nitric oxide (p = 0.49) or airway responsiveness (p = 0.20).
Uncontrolled airway inflammation causes a small decrease in the distensibility of the airways of asthmatics with airway hyper-responsiveness. The lack of association between airway responsiveness and airway distensibility, both before and after 12 weeks ICS treatment, suggests that airway remodelling does not contribute to airway hyper-responsiveness in asthma.

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HypothesisROLE OF PLASMA EXUDATION IN ASTHMATIC AIRWAYS

Abstract

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Respir Physiol

Eosinophil and neutrophil granulocytes in asthma

Pathology of the airway epithelium in asthma

Clin Respir Physiol

Alveolar macrophage and its participation m the inflammatory processes of allergic asthma

Clin Respir Physiol

Asthma as an axon reflex

Lancet

Microcirculation of the trachheobronchial tree

Nature

Vascular responses and their suppression drugs interfering with venular permeability

Effects and distribution of vagal capsaicin-sensitive substance P neurons with special reference to the trachea and lungs

Acta Physiol Scand

Inflammatory leakage of macromolecules from the vascular compartment into the tracheal lumen

Acta Physiol Scand

Tachykinins and nasal secretion

Effect of systemic glucocorticoid treatment on human nasal mediator release after antigen challenge

J Allergy Clin Immunol

The pathology of asthma with special reference to changes in the bronchial mucosa

J Clin Pathol

Variation in the composition of sputum in chronic chest diseases

Br J Exp Pathol

Soluble proteins of bronchopulmonary secretions from patients with cystic fibrosis asthma and bronchitis

Thorax

Hypothesis
ROLE OF PLASMA EXUDATION IN ASTHMATIC AIRWAYS