Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs

Abstract

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH 2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P Ͻ 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P Ͻ 0.01) and smooth muscle strips (P Ͻ 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs. bronchial hyperreactivity; respiratory mechanics; bronchoconstriction ASTHMATIC AIRWAYS ARE CHARACTERIZED by inflammation and airway hyperresponsiveness (AHR). AHR in vivo in asthmatic patients suggests that narrowing to provocative stimuli is increased. The mechanisms responsible for airway narrowing are thought to involve either altered responses within the airway wall [e.g., airway smooth muscle (ASM) and wall loads] or alterations in factors external to the airway wall (e.g., parenchymal forces). Over recent years, a number of animal models have been developed to examine the role of the airway and the lung in AHR. However, many aspects of airway physiology in asthma remain unclear, for example, the extent of narrowing in airways from asthmatic patients compared with controls and mechanisms by which airway narrowing might be altered in asthma.Smooth muscle contraction is a major determinant of airway diameter; therefore, AHR of asthma may be due to altered contractile behavior of ASM. However, the literature contains conflicting results, with only some studies indicating that ASM contraction is increased in animal models (11,16,30). Other studies provide clear evidence for a decrease in ASM contraction in sensitized animals (29). Responses of smooth muscle isolated from asthmatic patients show similar inconsistency (13, 28). Furthermore, attempts to show a relationship between the contractile properties of ASM and bronchial responsiveness in vivo have been unsuccessful (1,27,33). Despite extensive literature, the importance of ASM to hyperresponsiveness is still unclear, and it is not known whether ASM contraction in asthma is increased or not.The effect of load on ASM shortening is well established (15, 31). Alterations to the ASM load may affect airway narrowing and could be responsible for the exaggerated airway narrowing and AHR seen in asthma. Such alterations include structural changes ...

Structural changes in the airways in asthma: observations and consequences

“…In distinction to these findings, Ma and co-workers [114] have shown increased absolute shortening potential and velocity of shortening, as well as increased MLCK (myosin light chain kinase) gene expression, in asthmatic cells isolated from biopsies. Ex vivo studies of airway segments from hyperresponsive animals with structural changes induced by chronic allergen challenge have, paradoxically, sometimes shown decreased contractility or maximal shortening compared with controls [115,116]. Consistent with this, in an explant model in which smooth muscle hypertrophy and increased matrix was induced by cytokines, we showed decreased contractile responsiveness [80].…”

Airway narrowing in porcine bronchi with and without lung parenchyma

“…The similar diameters of airways in vivo and in vitro confirm a common anatomical location. Secondly, unlike previous studies [2,33], excised airway segments were exposed to a similar volume history seen in vivo by oscillating Ptm at amplitudes and frequencies mimicking ventilation. The authors recently demonstrated that bronchoconstrictor responses to EFS in porcine bronchial segments are enhanced after periods of pressure oscillation [34], emphasising the importance for recording airway narrowing under similar conditions in vivo and in vitro.…”

Farm animal models of organic dust exposure and toxicity

“…In the past decade, swine models have emerged as excellent tools to study human pulmonary diseases, including cystic fibrosis [11], respiratory distresses in neonates [12], and asthma [13,14]. The availability of the pig genome sequence [15,16] together with metagenomic datasets of organic dust microbiomes[17**,18**] provide insight for investigating and understanding mechanisms of clinical manifestations of farm exposures.…”