The impact of cigarette smoke (CS) exposure on the respiratory system can best be captured by evaluating changes in lung function coupled with assessments of morphology and structural composition. These measurements are both quantitative and can capture the extent of disease severity such as degree, pattern, and location of tissue destruction. To date, the relationship between these structure-function outcomes have been only partially characterized. A recent publication by Matz, J., et al (2022) provides an extremely thorough series of studies to further uncover the relationship between the pulmonary changes in structure and function following chronic cigarette smoke exposure (CSE) in an apolipoprotein E-deficient (Apoe-/-) mouse model.
Using the inExpose, Apoe-/- female mice were exposed to chronic nose-only mainstream CS starting at 8-weeks of age for 5-days a week over 24-weeks. Air matched controls were exposed for 5-days a week for 24-weeks to fresh air. A full 24-hours after the last exposure (CS or air), detailed lung function parameters were measured using the flexiVent. As this chronic exposure experiment spanned 24-weeks, this team even went an additional step further to measure the natural effects of aging on lung structure and function. This was done by comparing flexiVent lung function and morphology measurements between 8-week-old mice (exposure onset) and 32-week-old mice (exposure endpoint).
Following flexiVent analysis, the subjects were perfused and fixed for histology. MOVAT and PSR stains were taken at three cross sections of the left lobe: above, below, and at the main bronchi. Next both the airways and parenchyma were analyzed for the following:
» Airways: thickness and tissue composition (cytoplasm+nucleus, fibrin, elastin, high- and low- density collagen)
» Parenchyma: thickness, tissue fraction, mean linear intercept (Lm), equivalent airspace diameter (D0), heterogeneity, and tissue composition (cytoplasm+nucleus, fibrin, elastin, high- and low-density collagen)
Natural Aging Effects
Rn decreased in aging mice, particularly at Positive End Expiratory Pressures (PEEP) of 5 and 7 cmH2O.
G & H were decreased in aging mice at all PEEP levels (1, 3, 5, 7 cmH2O).
Central Rn was not significantly different between the CSE and air control groups. However, the peripheral H and G were both elevated in the CSE group.
Aged mice displayed a left and upward PV-loop curve shift, with larger hysteresis and quasi-static compliance compared to young mice.
CS-exposed mice displayed a downward and rightward shift of the PV-Loop curve, indicating a structurally stiffer lung. Cst was significantly smaller as well in the CS-exposed mice.
There was no increase in AHR in aged mice.
AHR was exacerbated at all concentrations (3-50 mg/mL) of Mch in the CSE mice.
Parenchyma: increase in high-density collagen
Airways: Increase in low-density collagen
Parenchyma: increase in low-density collagen
Airways: increase in low- and high- density collagen
Decrease in airway thickness
Increase in airway thickness
Parenchyma Airspace Morphology
Lm, D0, and heterogeneity increased with age
D0, airspace heterogeneity, and septal thickness increased with CSE (Lm was unchanged)
CSE over 24-weeks in female Apoe-/- mice impaired lung function with global stiffening of the lung as evidenced by a downward-rightward shift of the PV-loop, decreased Cst, with elevated H and G at all levels of Ppeep as compared to air exposed controls. These functional changes were corroborated with increased collagen deposition along with thickening of the airways and parenchyma. All of which highlight the ability of CSE in Apoe-/- to replicate features of CS-induced COPD which is typically understated in wildtype mice.
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