Acute mechanical forces cause deterioration in lung structure and function in elastase-induced emphysema

Abstract

. Acute mechanical forces cause deterioration in lung structure and function in elastase-induced emphysema. Am J Physiol Lung Cell Mol Physiol 303: L567-L574, 2012. First published August 1, 2012; doi:10.1152/ajplung.00217.2012The relation between the progression of chronic obstructive pulmonary disease (COPD) and exacerbations is unclear. Currently, no animal model of acute exacerbation of COPD (AECOPD) exists. The objectives of this study were to evaluate the effects of mechanical forces induced by deep inspirations (DIs) on short-term deterioration of lung structure and function to mimic AECOPD. At 2, 7, or 21 days after treatment with elastase, mice were ventilated with or without DIs (35 cmH 2O airway pressure for 3 s, 2 times/min) for 1 h. Functional residual capacity (FRC) was measured with body plethysmography, and respiratory compliance, resistance, and hysteresivity were obtained via forced oscillations. From hematoxylin and eosin-stained sections, equivalent airspace diameters (D), alveolar wall thickness (W t), number of septal ruptures (N sr), and attachment density (Ad) around airways were determined. FRC, compliance, and hysteresivity statistically significantly increased with time, and both increased due to DIs. Interestingly, DIs also had an effect on FRC, compliance, resistance, and hysteresivity in control mice. The development of emphysema statistically significantly increased D and Wt in time, and the DIs caused subtle differences in D. At 21 days, the application of DIs changed the distribution of D, increased Wt and Nsr, and decreased Ad. These results suggest that once a critical remodeling of the parenchyma has been reached, acute mechanical forces lead to irreversible changes in structure and function, mimicking COPD exacerbations. Thus, the acute application of DIs in mice with emphysema may serve as a useful model of AECOPD. AECOPD; mechanical stress; exacerbation; irreversibility CHRONIC OBSTRUCTIVE PULMONARY disease (COPD), including chronic bronchitis and emphysema, is a slowly developing and progressive disease with episodes of acute exacerbation (AE-COPD). According to the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) Summary (8a), AECOPD is an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. Most AECOPD is triggered by bacterial (36) or viral (35) infections, by pollutants (33), or by cold temperature (4). Moreover, severe exacerbation-related hospitalization is associated with an increased risk of mortality, even after discharge (8), with a heavy health care burden worldwide.While the frequency of AECOPD was shown to correlate with lung function decline (5, 34), irreversible structural changes behind the functional decline following AECOPD have been identified only recently. Tanabe et al. (38) reported that changes in the distribution of low-attenuation areas on computerized tomography images of COPD patients were consistent with the coalescence...

Scale dependence of structure-function relationship in the emphysematous mouse lung

“…It may be argued that such a maneuver may lead to septal wall failure and hence an artifact of the measurement protocol. However, in a recent study, we applied inflations to 35 cmH 2 O twice a minute for an hour to test the effects of extended mechanical forces on lung structure and function (Szabari et al, 2012 ). Since the differences between lung structure and function with and without such inflations were smaller than the difference between those at 2 and 7 days after treatment, we are confident that the brief inflations to 25 cmH 2 O would not noticeably affect the lung.…”

Proteomic differences with and without ozone-exposure in a smoking-induced emphysema lung model

“…Clinically, AECOPD is often observed in stage III or IV COPD; however, in the smoking-induced animal COPD model, the degree of COPD was equivalent to stage I or II of human COPD [ 28 ]. Second, we did not measure airway mechanics to confirm the smoking-induced COPD model, which has been performed in mouse and rat models by other researchers [ 29 , 30 ]. However, in the present study, the smoking-induced COPD model was appropriate because the MLIs were comparable to those in other studies [ 31 , 32 ].…”

Animal Models of Chronic Obstructive Pulmonary Disease Exacerbations: A Review of the Current Status

“…A wide variety of studies have highlighted the proteolytic activity of elastase in causing structural changes, such as higher mean linear intercept and alveolar enlargement both in mice [71][72][73][74][75] and in rats [76][77][78][79] (Table 2). Furthermore, several studies reported changes in ECM composition after elastase administration, such as disorganized elastin [80,81], degradation of proteoglycans [82], and abnormal collagen remodeling [83][84][85][86][87][88]. However, as in CS models, these effects are dependent on several factors, including strain; enzyme dose at each instillation; and number of elastase challenges (Figure 2).…”