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Can Retinoic Acid Ameliorate the Physiologic and Morphologic Effects of Elastase Instillation in the Rat?^*

^* From Genentech, Inc (Drs. Tepper and Tumas, Mr. Pfeiffer, Ms. Aldrich), South San Francisco, CA; the University of Iowa (Drs. Kern, Hoffman, and McLennan), School of Medicine, Iowa City, IA; and the University of California (Dr. Hyde), Davis, CA.

Correspondence to: Jeffrey Tepper, PhD, Immunology Research, MS-34, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080

	Introduction

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Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; FRC = functional residual capacity; RA = retinoic acid

Emphysema is a chronic obstructive lung disease that is characterized by enlarged airspaces and is accompanied by alveolar destruction. It is generally thought that alveoli, once damaged, cannot be repaired in the adult lung. However, compensatory lung growth with increased complexity of alveolar septa in adult dogs was reported¹ after 54% of their lung was removed (right pneumonectomy), a finding that was not reported when 42% of their lung was removed (left pneumonectomy). This study suggested that given the appropriate signal(s), the lung might be capable of growing new alveoli. The growth of new alveoli also was reported in postnatal rats treated with systemic retinoic acid (RA) after the suppression of alveolar growth by dexamethasone.² However, the necessary components for alveolar septation are available in young rats. More recently, new alveolar growth was reported in adult rats that had been treated systemically with RA after intratracheal elastase-induced destruction of alveoli.³ We asked whether the finding of new alveolar septation after RA treatment could be replicated and whether this repair produced an improvement in the lung function of rats whose lungs were damaged by elastase instillation, which is a model of emphysema.

	Materials and Methods

TOP Introduction Materials and Methods Results Conclusions References

 
Adult male Sprague-Dawley rats (90 days old at the start of the experiment) received either saline solution or 1,000 IU porcine elastase on days 0 and 14. The saline solution or elastase was delivered intratracheally using a microspray device (Penn Century; Philadelphia, PA) with a mean particle size of 15 to 20 µm. Nine weeks after the first instillation, the rats were treated either with all-trans-RA (500 µg/kg, intraperitoneally, daily for 2 weeks) in tetraglycol vehicle or with vehicle alone. At weeks 3, 6, 9, and 11, a dimensionless, noninvasive indicator of airflow obstruction (Buxco Electronics; Sharon, CT) was evaluated.⁴ Just prior to killing the rats at week 11, a battery of pulmonary function tests was performed.⁵ The tests included assessment of tidal breathing and breathing mechanics; respiratory system peak compliance, between 25 and -20 cm H₂O; forced expiratory flow rates, between 25 and -40 cm H₂O; multibreath diffusing capacity of the lung for carbon monoxide (DLCO), using a gas dilution of 1% carbon monoxide; functional residual capacity (FRC) using end-tidal occlusion (Boyle’s Law method); and other subdivisions of lung volume using neon gas dilution (0.5%). After testing, the rats were perfused with saline solution (lungs were inflated with air at 30 cm H₂O), were given a volume history, and were intravascularly fixed (Karnovsky’s fixative) at 12 cm H₂O. Twenty-four hours later, the lungs were moved to formalin and were stored for sectioning. At 5 months, the fixed lungs were imaged with an electron-beam high-resolution CT scanner (model C-150XL; Imatron; South San Francisco, CA) using a standard 100-ms axial scan at 0.5 mm of resolution. Volume and density were determined after reconstruction using an extra sharp kernel. For all measurements, preplanned multiple comparisons were tested after a significant (p < 0.05) interaction term was obtained in a two-way analysis of variance.

	Results

TOP Introduction Materials and Methods Results Conclusions References

 
No significant effect on body weight was observed among groups throughout the 11-week study. During that period, the elastase-instilled rats always showed a larger pause than the saline solution-instilled mice, suggesting that the elastase-instilled rats had airflow obstruction. After 2 weeks of RA treatment, the rats treated with elastase plus vehicle showed significant progression of the obstruction, while those treated with elastase plus RA were unchanged from their previous value (Table 1 ). Elastase instillation increased residual volume and total lung capacity compared to saline solution instillation. RA treatment significantly reduced these changes in lung volumes compared to treatment with elastase plus vehicle, while vital capacity was nonsignificantly reduced. Peak respiratory system compliance was increased and DLCO was decreased (after correction for differences in lung volumes), as would be expected in this emphysema model. Forced expiratory flow rates were also lower at all lung volumes. However, RA had no effect on these parameters in the elastase-instilled rats. Lung volume measurement by CT scan correlated highly with physiologic measurements of FRC (r = 0.52; p < 0.03). Density measurements from the CT scan, obtained by detecting differences in trapped gas remaining in the lungs fixed with formalin, indicated that the lungs of rats treated with elastase plus RA had densities between those treated with elastase plus vehicle and those treated with saline solution. However, these differences were not significant, in part due to the smaller number of rats evaluated (n = 3 to 7 per group).

	Conclusions

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	Footnotes

 
This research was supported by Genentech, Inc.

	References

TOP Introduction Materials and Methods Results Conclusions References

 

1. Hsia, CCW, Heranzo, LF, Fryder-Doffey, F, et al (1994) Compensatory lung growth occurs in adult dogs after right pneumonectomy. J Clin Invest 94,405-412
2. Massaro, G, Massaro, D (1996) Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol 14,L305-L310
3. Massaro, G, Massaro, D (1997) Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med 3,675-677[CrossRef][ISI][Medline]
4. Tepper, JS, Yuan, F, Pfeiffer, JW, et al (1998) Airflow obstruction in murine allergic inflammation: the effectiveness of albuterol vs. dexamethasone [abstract]. Am J Respir Crit Care Med 157,A822
5. Tepper, JS, Costa, DL, Winsett, DW, et al (1993) Evidence of transient airway obstruction in the rat after a chronic exposure to an ambient pattern of nitrogen dioxide. Fundam Appl Toxicol 20,88-96[Medline]

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