Hyperoxia-induced Airway Remodeling in Immature Rats: Correlation with Airway Responsiveness

Abstract

We recently found that exposure of 21-day-old rats to hyperoxia (> 95% O2 for 8 days) significantly increased in vivo airway cholinergic responsiveness and that O2 exposure also increased airway epithelial and smooth muscle layer thicknesses in a separate cohort of animals. There was substantial variation in the magnitude of both the functional and structural responses to hyperoxia. The present study was designed to test whether the magnitude of O2-induced airway remodeling could account for individual differences in airway responsiveness after O2 exposure, as well as for the difference in responsiveness between air- and O2-exposed animals. We assessed in vivo airway responsiveness to aerosolized acetylcholine (ACh) and airway architecture in 14 O2- and 5 air-exposed, immature rats. Total respiratory system resistance was determined using a plethysmographic method. The mean thicknesses and fractional areas of the airway epithelial and smooth muscle layers were determined by contour tracing using a digitizing pad and microcomputer. Both the small (circumference < 1,000 microns) and central (circumference 1,000 to 4,000 microns) airways were studied. For O2-exposed rats, individual values of EC200 ACh correlated negatively with small airway smooth muscle layer thickness (r = -0.59, p < 0.05; ANOVA), small airway smooth muscle layer fractional area (r = -0.75, p < 0.01), small airway epithelial thickness (r = -0.54, p < 0.05), small airway epithelial fractional area (r = -0.69, p < 0.01), and central airway smooth muscle layer thickness (r = -0.53, p < 0.05). When both air- and O2-exposed animals were considered, EC200 ACh correlated negatively with all eight parameters of airway layer thickness and fractional area.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal Hyperoxia Enhances the Inflammatory Response in Adult Mice Infected with Influenza A Virus

“…Intriguingly, some of these changes are permanent, as normal lung structure and function are not restored when newborn animals are returned to room air (9)(10)(11). Hyperactive airways with increased thickness of the underlying smooth muscle have also been reported in 21-day-old rats exposed to and recovered from greater than 95% oxygen (12,13). We reported that exposure of newborn mice to greater than 85% oxygen between Postnatal Days 1 and 4 causes permanent alveolar simplification and altered lung compliance in adult mice (14,15).…”

Acute Hyperoxic Injury Attenuates the Relaxing Effects of “Loop” Diuretics and Salbutamol on Large Airways of Newborn Guinea Pigs

“…Studies examining mechanisms of hyperoxia-induced airway hyperresponsiveness havc focused on contractile mechanisms (20)(21)(22)28) although excessive airway narrowing could be due to impaired relaxation (29). The most important finding of this study was that in newborn guinea pig airways, in vivo exposure to hyperoxia decreased the relaxing ability of loop diuretics, ethacrynic acid and furosemide, and the P,-adrenergic receptor agonist salbutamol.…”

“…Hyperoxia is known to cause pulmonary pathology and dysfunction in many animals (21)(22)(23)(24)27), although the mechanism of this injury is not fully understood. Studies examining mechanisms of hyperoxia-induced airway hyperresponsiveness havc focused on contractile mechanisms (20)(21)(22)28) although excessive airway narrowing could be due to impaired relaxation (29).…”

“…However, patients with normal airways are rarely treated in the clinical setting. Thus, the potential clinical relevance of furosemide mediated airway relaxation must be established in various pathologic conditions, such as hyperoxia-induced airway injury, because hyperoxic exposure increases maximum airway contractility in newborn guinea pigs (20) and immature rats (21,22). On the other hand, little is known about the effects of hyperoxia on airway relaxation.…”

“…A single investigator (G.A.M.) performed all observations in an attempt to obtain a uniform set of subjects for study, because previous investigators (21,22,24) have described variable pathologic and functional results when exposure time was set a puiori. Control animals were matched for age and similarly reared in room air.…”