Docosatetraenoyl LPA is Elevated in Exhaled Breath Condensate in Idiopathic Pulmonary Fibrosis

Sydney B Montesi; Susan K Mathai; Laura N Brenner; Irina A Gorshkova; Evgeny V Berdyshev; Andrew M Tager; Barry S Shea

Disclosures

BMC Pulm Med. 2014;14(5) 

In This Article

Background

Idiopathic pulmonary fibrosis is a progressive and ultimately fatal disease in which normal lung is replaced by fibrous scar tissue. The cause of the disease is unknown; however, exposure to refluxed gastric acid, occupational exposures, and viral infections have been postulated as inciting insults.[1–3] The average duration from diagnosis to time of death is 2–3 years.[4] Diagnosis is made either by pathology consistent with usual interstitial pneumonia or radiographic findings showing areas of fibrosis and honeycombing in the absence of an alternate diagnosis.[5] Once the diagnosis of IPF is made limited options exist for treatment except for lung transplantation.

Recent advances have occurred in our understanding of the mechanisms involved in IPF pathogenesis. Specifically, aberrant wound healing responses to tissue injury, such as epithelial cell apoptosis, increased vascular permeability, extravascular coagulation, and fibroblast migration and activation, have all been implicated in the development of lung fibrosis.[6,7] Research efforts have focused on identifying molecular pathways central to the progression from normal to fibrotic lung, as a better understanding of such pathways may provide potential targets for pharmacologic therapy and biomarkers to aid in diagnosis or prognosis.[7] One such area of interest involves the role of lysophosphatidic acid (LPA) in the development and progression of pulmonary fibrosis.

LPA is a biologically active lysophospholipid that has been shown to mediate numerous biological processes thought to contribute to tissue fibrosis.[7] Structurally, LPA consists of glycerol-phosphate with a single fatty acid esterified at the sn-1 or sn-2 position. There are numerous LPA species present in biological fluids, identified by the length and degree of saturation of the fatty acid moiety.[8] The majority of extracellular LPA is produced from lysophosphatidylcholine (LPC) by the enzyme autotaxin (also known as lysophospholipase D).[9,10] LPA's activity is mediated by interaction with specific G protein-coupled receptors, six of which have been definitively identified (LPA1-6).[7,11,12] The role of LPA and its receptors has been investigated in the development of fibrosis in multiple organ systems, including the lung, liver, kidneys, skin and peritoneum.[13–17] In the setting of lung injury, LPA has been shown to contribute to epithelial cell death, increased vascular permeability, and fibroblast migration and persistence via interaction with the LPA1 receptor, and genetic deficiency or pharmacologic inhibition of LPA1 confers protection against bleomycin-induced lung fibrosis in mice.[13,18,19] Furthermore, LPA is elevated in the BAL fluid of IPF patients and contributes to fibroblast migration into the injured airspaces in this disease.[13] Based on the apparent importance of the LPA-LPA1 pathway for the development of lung fibrosis, a Phase II clinical trial of an oral LPA1 antagonist for the treatment of IPF has recently been initiated (ClinicalTrials.gov identifier: NCT01766817). Recent evidence indicates that the LPA2 receptor can also mediate profibrotic effects of LPA, such as activation of latent transforming growth factor-β (TGF-β), and genetic deficiency of this receptor also results in protection against the development of lung fibrosis in mice.[13,20,21]

Given its potentially important and central role in the development of pulmonary fibrosis, LPA is not only a therapeutic target but also a potential biomarker in IPF. While elevated LPA levels have been detected in the BAL from IPF patients,[13] the extent to which LPA is present and detectable in exhaled breath condensate (EBC) is not known. EBC has become an area of interest for potential biomarker analysis in respiratory diseases.[22] Collection of EBC can be performed in a low-cost and non-invasive manner. For the detection of certain biologic molecules, correlation has been demonstrated between EBC and BAL results, though further research is needed.[23] In addition to volatile gases, EBC contains nonvolatile particles representing airway and alveolar lining fluid contents.[24] The ability to analyze components from the lining of the respiratory epithelium offers great potential for biomarker discover. EBC has been studied in different respiratory diseases, including asthma and COPD.[25,26] However, few studies have analyzed EBC in the setting of interstitial lung disease, specifically IPF.[27,28] If LPA were detectable in EBC, it may provide information about the disease and/or the disease course. In this study we sought to assess for the presence of LPA in plasma and EBC and determine if differences exist in the amount of LPA in subjects with IPF versus controls.

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