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Am J Physiol Lung Cell Mol Physiol (November 26, 2003). doi:10.1152/ajplung.00335.2003
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Submitted on September 18, 2003
Accepted on November 19, 2003

Lysosomal Acid Lipase Deficiency Causes Respiratory Inflammation and Destruction in the Lung

Xuemei Lian1, Cong Yan2*, Li Yang3, Yan Xu3, and Hong Du4

1 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; The Graduate Program for Pediatrics, Chongqing University of Medical Science, Chongqing, China
2 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; The Graduate Program for Molecular and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
3 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
4 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

* To whom correspondence should be addressed. E-mail: Cong.Yan{at}cchmc.org.

The functional roles of neutral lipids are poorly understood in the lung. Blocking cholesteryl ester and triglyceride metabolism in the lysosomal acid lipase gene knock-out mice (lal-/-) resulted in a high level of neutrophil influx in the lungs as early as 2 months old. The numbers of broncho-alveolar macrophages appeared foamy and gradually increased with age progression. Affymetrix GeneChip array analyses of lung mRNA showed increased levels of pro-inflammatory cytokines (including IL-1{beta}, IL-6 and TNF{alpha}) and matrix metalloproteinases (including MMP8, MMP9 and MMP12) expression in lal-/- mice. With age progression, some areas of lal-/- mice developed severe abnormal cell proliferation and alveolar remodeling. In other areas, alveolar destruction (emphysema) was observed. In addition, Clara cell hypertrophy and hyperplasia were developed in conducting airways. The pathophysiological phenotypes in the lal-/- mouse lungs became more severe in an age-dependent fashion. The studies support a concept that neutral lipid metabolites play essential roles in pulmonary homeostasis, inflammatory responses, remodeling and injury repairing.




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