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Am J Physiol Lung Cell Mol Physiol 286: L801-L807, 2004. First published November 26, 2003; doi:10.1152/ajplung.00335.2003
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Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung

Xuemei Lian,1,4 Cong Yan,2,3 Li Yang,2 Yan Xu,2 and Hong Du1

1Division of Human Genetics, 2Division of Pulmonary Biology, and 3Graduate Program for Molecular and Developmental Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039; and 4Graduate Program for Pediatrics, Chongqing University of Medical Sciences, Chongqing 400016, China

Submitted 18 September 2003 ; accepted in final form 19 November 2003

The functional roles of neutral lipids are poorly understood in the lung. Blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) resulted in a high level of neutrophil influx in the lungs as early as 2 mo of age. Bronchoalveolar macrophages appeared foamy and gradually increased in number with age progression. Affymetrix GeneChip array analysis of lung mRNA showed increased levels of proinflammatory cytokine (including IL-1{beta}, IL-6, and TNF-{alpha}) and matrix metalloproteinase (including MMP-8, MMP-9, and MMP-12) 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 (i.e., emphysema) was observed. In addition, Clara cell hypertrophy and hyperplasia developed in conducting airways. The pathophysiological phenotypes in the lal-/- mouse lungs became more severe with increasing age. The studies support the concept that neutral lipid metabolites play essential roles in pulmonary homeostasis, inflammatory responses, remodeling, and injury repair.

neutral lipid; remodeling; emphysema


Address for reprint requests and other correspondence: H. Du, Div. of Human Genetics, and C. Yan, Div. of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: Hong.Du{at}cchmc.org and Cong.Yan{at}cchmc.org).




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