Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung

Abstract

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-1beta, 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.

Pathogenesis of Emphysema: From the Bench to the Bedside

“…Blockage of neutral lipid metabolism has been shown to cause emphysema, increased lung neutrophils and macrophages, increased expression of proinflammatory cytokines and MMPs, and Clara cell hypertrophy and hyperplasia in a lysosomal acid lipase knockout mouse model (18). Emphysema-and inflammation-related remodeling is also seen in the absence of surfactant proteins A, C, and D with findings similar to lysosomal acid lipase knockout mice (19).…”

“…For example, vascular endothelial growth factor, an endothelial cell survival factor, is abundant in the lung, and its blockade results in apoptosis-dependent airspace enlargement (21)(22)(23). In contrast, apoptosis of type II pneumocytes may compromise the production of surfactant, which produces changes similar to emphysema in animal models (18,19). Furthermore, the maintenance of the alveolar structure depends upon the interaction between different cell types and the lung's matrix.…”

Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function

“…4,5 Briefly, frozen tissue sections were prepared from lal ϩ/ϩ or lal Ϫ/Ϫ thymus and spleen after a standard cryostat procedure. Tissue section slides were stained with oil red O solution (0.5% in propylene glycol) in a 60°C oven for 10 minutes and placed in 85% propylene glycol for 1 minute.…”

“…Altered differentiation and dysfunction of myeloid lineage cells (macrophages, neutrophils) have been reported previously to contribute to pathogenic progression in lal Ϫ/Ϫ mice. 4,7,8 In these mice, Kupffer cells (liver macrophages), bronchoalveolar macrophages, and intestinal macrophages appeared abnormal (foamy) with neutral lipid accumulation and aberrant cytokine/chemokine secretion. 4,5,8 In a cell type-specific rescue experiment, a myeloid-specific doxycycline-inducible transgenic mouse system was generated to specifically express wild-type hLAL in lal Ϫ/Ϫ myeloid lineage cells under the control of the c-fms promoter.…”

“…For example, in the lung, cytokines/chemokines, endopeptidases (eg, matrix metalloproteinases), apoptosis inhibitors, transcription factors, and oncogenes were expressed aberrantly. 4,7 The Affymetrix GeneChip Microarray study demonstrated a correlation between gene profile changes and pathogenic progression in the lal Ϫ/Ϫ lung in an age-dependent manner. Some of these genes are downstream targets for lipid mediators (eg, peroxisome proliferator-activated receptor gamma), which can be activated by neutral lipid metabolic derivatives (hormonal ligands).…”