Lysophosphatidic acid in airway function and disease.
Lysophosphatidic acid (LPA) is a bioactive lipid mediator and important component of serum. Studies over the past several years which have documented diverse effects of LPA on multiple types of airway cells and which suggest possible involvement of LPA in lung disease are reviewed here. LPA enhances contractility of airway smooth muscle. It also stimulates proliferation of cultured airway smooth muscle cells and exhibits a striking synergism with epidermal growth factor (EGF) for stimulating mitogenesis. Recent studies of the molecular components and signaling pathways mediating synergism are described, including LPA-induced upregulation of EGF receptors and activation of multiple transcription factors by both LPA and EGF. A model for the effects of LPA and EGF on mitogenesis that includes EGF receptor upregulation and synergism between Ras and Rho for activation of the transcription factor AP-1 is presented. LPA stimulates fibronectin secretion and filopodia extension in airway epithelial cells as well as proliferation and collagen gel contraction by lung fibroblasts. A hypothesis for LPA involvement in the airway repair and remodeling, which contribute to the pathology of asthma and other airway diseases, is presented, and future directions for research into the roles of LPA in airway function and disease are suggested.
Toews
Myron L
ML
Department of Pharmacology, University of Nebraska Medical Center, 986260 Nebraska Medical Center, Omaha, NE 68198-6260, USA. mtoews@unmc.edu
Ediger
Tracy L
TL
Romberger
Debra J
DJ
Rennard
Stephen I
SI
D000818:Animals; D001249:Asthma / Q000503:physiopathology; D002455:Cell Division; D004815:Epidermal Growth Factor / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020545:Respiratory Mucosa / Q000502:physiology; D012143:Respiratory Physiological Phenomena; D012140:Respiratory Tract Diseases / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D008246:Lysophospholipids; D004815:Epidermal Growth Factor