Review
Lysophosphatidic acid in airway function and disease

https://doi.org/10.1016/S1388-1981(02)00177-4Get rights and content

Abstract

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.

Introduction

For many laboratories, interest in lysophosphatidic acid (LPA) began with its identification as the “serum factor” mediating a response of interest in that laboratory. Subsequent follow-up studies in these and other laboratories then led to important insights on the receptors and signaling pathways mediating the diverse effects of LPA and on its likely physiological and clinical significance, as summarized in multiple chapters in this volume and in other reviews [1], [2], [3], [4]. Similarly, our interest in LPA began when we identified it as the serum factor mediating serum-induced “sensitization” of cyclic AMP (cAMP) responses in several cell types, including airway smooth muscle cells. Subsequent studies in our laboratories have focused on the effects of LPA on various cells from the airway, including airway smooth muscle cells, airway epithelial cells and lung fibroblasts, all of which are summarized in this review. The responses identified to date point to a potential role of LPA as a mediator of airway “repair” and “remodeling”, processes that are now thought to be a major component of the pathology of asthma and chronic obstructive pulmonary disease [5], [6], [7]. Our studies of a striking synergism between LPA and receptor tyrosine kinase (RTK) growth factors such as epidermal growth factor (EGF) in stimulating airway smooth muscle cell mitogenesis have identified mechanisms that are likely to contribute to the prominent effects of LPA on growth regulation, not only of airway smooth muscle but also of vascular smooth muscle and other contractile cell types throughout the body. We suggest that further investigation of the presence and functions of LPA in normal and diseased human airways may point the way to new therapeutic approaches for the treatment or prevention of asthma and other airway diseases.

Section snippets

Regulation of classical second messenger pathways

Our studies of LPA began with its identification as the serum factor mediating “sensitization” of cAMP responses in two glial cell lines [8]. Sensitization is an increase in the responsiveness of the receptor-stimulated adenylyl cyclase system that can occur during exposure to agents that signal through Gi to inhibition of adenylyl cyclase or through Gq to the phosphoinositide (PI) hydrolysis pathway [9]. We compared the abilities of a wide variety of cell types to exhibit sensitization to

EGF receptor regulation

Multiple lines of evidence suggested that synergism was due to LPA enhancement of EGF signaling rather than EGF enhancement of LPA signaling. In particular, a mitogen washout experiment [29] showed that DNA synthesis in response to LPA could be observed at 24 h following as little as 6-h exposure to LPA, whereas significant DNA synthesis at 24 h was observed for EGF only with exposure for at least 8–12 h. Synergism between LPA and EGF also became apparent only following 12-h exposure, similar

LPA effects on airway epithelial cells

Although our recent studies have focused on LPA regulation of airway smooth muscle cells, we have also documented a variety of effects of LPA on other lung cells, effects which are also likely to be of clinical relevance in airway disease. LPA stimulated production of the extracellular matrix molecule fibronectin in both bovine bronchial epithelial cells (BBECs) and in human bronchial epithelial cells [47]. Fibronectin mRNA was also increased, at least for BBECs, suggesting that LPA increases

LPA, airway repair and remodeling, and asthma: a hypothesis

Taken together, the effects of LPA on airway cells and tissue preparations summarized above lead us to hypothesize that LPA may be a contributor to the pathogenesis of asthma in particular and perhaps to other airway diseases as well. The release of LPA from platelets activated at a site of injury and its ability to promote fibroblast proliferation and contraction have led to the widely held view that LPA is a mediator of wound repair, and recent studies have provided evidence that LPA can in

References (65)

  • W.H. Moolenaar

    Exp. Cell Res.

    (1999)
  • W.H. Moolenaar

    Curr. Opin. Cell Biol.

    (1995)
  • S.I. Rennard

    Allergol. Inter.

    (1998)
  • T.L. Ediger et al.

    Biochim. Biophys. Acta

    (2001)
  • K. Jalink et al.

    J. Biol. Chem.

    (1990)
  • W.H. Moolenaar et al.

    Curr. Opin. Cell Biol.

    (1997)
  • K.L. Abbott et al.

    J. Mol. Cell. Cardiol.

    (2000)
  • M. Shahrestanifar et al.

    J. Biol. Chem.

    (1999)
  • S.A. Sagi et al.

    J. Biol. Chem.

    (2001)
  • T.S. Panetti et al.

    Prostaglandins Other Lipid Mediat.

    (2001)
  • M. Parizi et al.

    Exp. Cell Res.

    (2000)
  • F. Grinnell et al.

    J. Biol. Chem.

    (1999)
  • T. Mio et al.

    J. Lab. Clin. Med.

    (2002)
  • S. Orlati et al.

    Arch. Biochem. Biophys.

    (2000)
  • A. Sturm et al.

    Gastroenterology

    (1999)
  • K. Racke et al.

    Pulm. Pharmacol Ther.

    (2000)
  • Z. Shen et al.

    Gynecol. Oncol.

    (1998)
  • K. Fukami et al.

    J. Biol. Chem.

    (1992)
  • J.J.A. Contos et al.

    Mol. Pharmacol.

    (2000)
  • E.J. Goetzl et al.

    FASEB J.

    (1998)
  • J. Bousquet et al.

    Am. J. Respir. Crit. Care Med.

    (2000)
  • D.M. Kreps et al.

    FASEB J.

    (1993)
  • M.L. Toews et al.
  • M. Nogami et al.

    Mol. Pharmacol.

    (1995)
  • T.L. Ediger, Doctoral Dissertation, University of Nebraska Medical Center, Omaha, NE,...
  • M.L. Toews et al.

    J. Appl. Physiol.

    (1997)
  • A. Tokumura et al.

    Lipids

    (1978)
  • A. Tokumura et al.

    J. Pharm. Pharmacol.

    (1991)
  • A. Tokumura et al.

    Arch. Int. Pharmacodyn. Ther.

    (1980)
  • A.L. James et al.

    Am. Rev. Respir. Dis.

    (1989)
  • C.A. Hirshman et al.

    Am. J. Physiol.: Lung Cell. Mol. Physiol.

    (1999)

    • Cited by (0)

    View full text
    Copyright © 2002 Elsevier Science B.V. All rights reserved.