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1 Department of Medicine, Georgetown University School of Medicine, Washington, DC, USA
2 Department of Pediatrics, Georgetown University School of Medicine, Washington, DC, USA
3 Department of Biology, Georgetown University, Washington, DC, USA
4 Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
* To whom correspondence should be addressed. E-mail: massarod{at}georgetown.edu.
Calorie restriction, followed by ad libitum refeeding, results, respectively, in loss and regeneration of pulmonary alveoli. We now show 35% of alveoli are lost within 72 h of onset of calorie restriction (2/3 decreased daily chow intake), an additional 12% of alveoli are lost over a subsequent 12 days of calorie restriction. Tissue necrosis was not seen. Within 72 h of refeeding, after 15 days of calorie restriction, the number of alveoli returns to pre-calorie restriction values. Microarray lung gene profiling, in conjunction with western and RNase Protection Assay, demonstrate an increase of granzyme and caspase gene expression 2-3 h after onset of calorie restriction. By 12 h, granzyme and caspase expression are no longer increased but tumor necrosis factor death receptor expression is elevated. At 336 h, Fas death receptor expression is increased. Because granzymes are found only in cytotoxic lymphocytes (CTLs) and natural killer (NK) cells, we suggest calorie restriction activates these cells initiating a series of molecular events that result in alveolar destruction. The evidence of involvement of CTLs and NK cells, and the absence of necrosis, are similar to alveolar destruction in chronic obstructive pulmonary disease.
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