Effects of airway smooth muscle contraction and inflammation on lung tissue compliance

There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's parenchyma stiffens or loosens, respectively. However, whether K is affected by other common features of respiratory diseases, such as inflammation and airway smooth muscle (ASM) contraction, is unknown. Herein, male C57BL/6 mice were treated intranasally with either saline or lipopolysaccharide (LPS) at 1 mg/Kg to induce pulmonary inflammation. They were then subjected to either a multiple or a single-dose challenge with methacholine to activate ASM to different degrees. A quasi-static pressure-driven partial pressure-volume maneuver was performed before and after methacholine. The Salazar-Knowles' equation was then fitted to the deflation limb of the P-V loop to obtain K, as well as the parameter A, an estimate of lung volume (inspiratory capacity). The fitted curve was also used to derive the quasi-static elastance (Est) at 5 cmH2O. The results demonstrate that LPS and both methacholine challenges increased Est. LPS also decreased A, but did not affect K. In contradistinction, methacholine decreased both A and K in the multiple-dose challenge, while it decreased K but not A in the single-dose challenge. These results suggest that LPS increases Est by reducing the open lung volume (A) and without affecting tissue compliance (K), while methacholine increases Est by decreasing tissue compliance with or without affecting lung volume. We conclude that lung tissue compliance, assessed using the parameter K of Salazar-Knowles' equation, is insensitive to inflammation but sensitive to ASM contraction.

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ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00372.2014 ◽

2015 ◽

Vol 309 (7) ◽

pp. L736-L746 ◽

Cited By ~ 21

Author(s):

David I. Kasahara ◽

Joel A. Mathews ◽

Chan Y. Park ◽

Youngji Cho ◽

Gabrielle Hunt ◽

...

Keyword(s):

Smooth Muscle ◽

Muscle Contraction ◽

Airway Smooth Muscle ◽

Airway Hyperresponsiveness ◽

Matrix Protein ◽

Pulmonary Inflammation ◽

Inflammatory Cells ◽

Smooth Muscle Contraction ◽

Airway Smooth Muscle Cells ◽

Wild Type

Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1+/−, and ROCK2+/− mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2+/− mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2+/− mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1+/− but not ROCK2+/− mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1+/− or ROCK2+/− mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction.

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Effects of lung volume on airway resistance during induced constriction in papain-treated rabbits

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.6.1872 ◽

1996 ◽

Vol 80 (6) ◽

pp. 1872-1879 ◽

Cited By ~ 3

Author(s):

T. Nagase ◽

H. Matsui ◽

E. Sudo ◽

T. Matsuse ◽

M. S. Ludwig ◽

...

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Lung Volume ◽

Airway Resistance ◽

Transpulmonary Pressure ◽

Airway Narrowing ◽

Tissue Resistance ◽

Before And After ◽

Baseline Conditions ◽

Different Levels

It has been reported that both the elasticity of the cartilage and airway-parenchymal interdependence can modify shortening of the airway smooth muscle and airway narrowing during induced constriction. We hypothesized that induced softening of the cartilage could alter airway compliance and/or the forces of mechanical interdependence, resulting in an increased degree of airway narrowing in response to a contractile stimulus. To test this hypothesis, we compared the effects of changing lung volume on airway resistance (Raw) under baseline conditions and during methacholine (MCh)-induced constriction in papain-treated (n = 6) and control rabbits (n = 6). With use of the alveolar capsule technique, Raw was directly measured under baseline conditions at different levels of end-expiratory transpulmonary pressure (Ptp = 4-12 cmH2O). Then aerosolized MCh was delivered (0.2-25 mg/ml) and measurements were performed at different levels of Ptp (4 and 12 cmH2O). From measured tracheal flow and tracheal and alveolar pressure in open-chest animals during mechanical ventilation (tidal volume = 6 ml/kg, breathing frequency = 1 Hz), we calculated Raw by subtracting tissue resistance from lung resistance. Papain treatment significantly increased Raw both under baseline conditions and after induced constriction. We found that increasing Ptp decreased Raw before and after MCh in both groups; however, the effects of changing Ptp on Raw were less in papain-treated animals. These observations suggest that both cartilage elasticity and mechanical interdependence are important determinants of airway smooth muscle shortening. The observation that volume dependence of Raw was less in papain-treated animals is consistent with the hypothesis that papain effects significant changes in the parenchymal attachments.

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Effect of time-varying load on degree of bronchoconstriction in the dog

Journal of Applied Physiology ◽

10.1152/jappl.1998.85.4.1464 ◽

1998 ◽

Vol 85 (4) ◽

pp. 1464-1470 ◽

Cited By ~ 12

Author(s):

Norihiro Shinozuka ◽

Jean-Pierre Lavoie ◽

James G. Martin ◽

Jason H. T. Bates

Keyword(s):

Smooth Muscle ◽

Muscle Contraction ◽

Airway Smooth Muscle ◽

Lung Volume ◽

In Vitro Study ◽

Smooth Muscle Contraction ◽

Lung Mechanics ◽

Muscle Shortening

It is well established that the degree of airway smooth muscle shortening produced by a given dose of bronchial agonist is greatly affected by lung volume. The airways are tethered by parenchymal attachments, the tension of which increases progressively with lung volume, thereby presenting a commensurately increasing hindrance to smooth muscle contraction. Earlier studies (P. F. Dillon, M. O. Aksoy, S. P. Driska, and R. A. Murphy. Science 211: 495–497, 1981) presented evidence that smooth muscle contraction initially involves rapidly cycling cross bridges, which then change to noncycling (latch) bridges. They also suggested that most of the muscle shortening occurs during the early rapid cross-bridge phase. This implies that smooth muscle subject to a given load early in contraction should shorten less than when it is subject to the same load later on. An in vitro study (W. Li and N. L. Stephens. Can. J. Physiol. Pharmacol. 72: 1458–1463, 1994) obtained support for this notion. To test this hypothesis in vivo, we measured the changes in lung impedance at 1 and 6 Hz produced in dogs by a bolus intravenous injection of methacholine when lung volume was increased for 10 s at different times after injection. We found that the changes in mechanics were greatly inhibited, whereas lung volume was elevated. However, when lung volume was returned to its initial level, the lung mechanics continued to change at a rate unaffected by the preceding volume change. We conclude that temporary mechanical inhibition of airway smooth muscle shortening in the normal dog in vivo merely delays an otherwise normal course of contraction.

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