Docosatetraenoyl LPA is elevated in exhaled breath condensate in idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective medical therapies. Recent research has focused on identifying the biological processes essential to the development and progression of fibrosis, and on the mediators driving these processes. Lysophosphatidic acid (LPA), a biologically active lysophospholipid, is one such mediator. LPA has been found to be elevated in bronchoalveolar lavage (BAL) fluid of IPF patients, and through interaction with its cell surface receptors, it has been shown to drive multiple biological processes implicated in the development of IPF. Accordingly, the first clinical trial of an LPA receptor antagonist in IPF has recently been initiated. In addition to being a therapeutic target, LPA also has potential to be a biomarker for IPF. There is increasing interest in exhaled breath condensate (EBC) analysis as a non-invasive method for biomarker detection in lung diseases, but to what extent LPA is present in EBC is not known. Methods: In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess for the presence of LPA in the EBC and plasma from 11 IPF subjects and 11 controls. Results: A total of 9 different LPA species were detectable in EBC. Of these, docosatetraenoyl (22:4) LPA was significantly elevated in the EBC of IPF subjects when compared to controls (9.18 pM vs. 0.34 pM; p = 0.001). A total of 13 different LPA species were detectable in the plasma, but in contrast to the EBC, there were no statistically significant differences in plasma LPA species between IPF subjects and controls. Conclusions: These results demonstrate that multiple LPA species are detectable in EBC, and that 22:4 LPA levels are elevated in the EBC of IPF patients. Further research is needed to determine the significance of this elevation of 22:4 LPA in IPF EBC, as well as its potential to serve as a biomarker for disease severity and/or progression

Fibrocytes in Human Lung Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a rapidly progressing interstitial lung disease (ILD) with an unclear etiology and poorly understood pathogenesis. IPF has no known curative treatment and a grim prognosis. One emerging area of interest in the field of fibrosing diseases is the role that bone marrow-derived cells, specifically fibrocytes, play in lung repair and remodeling. Derived from circulating CD14+ progenitors in the peripheral blood, these cells are identified by CD45 and pro-Collagen I co-expression. There exist scant data regarding fibrocytes derived from the peripheral blood in patients with pulmonary fibrosis. We hypothesized that (1) fibrocyte levels in the peripheral blood of patients with IPF would be greater than in patients with non-specific interstitial pneumonia (NSIP), the second most common type of ILD; (2) intrapulmonary fibrocyte levels would vary significantly between patients with IPF and non-IPF pathology; and (3) plasma from subjects with high fibrocyte levels would reveal a profile of immunomediators differing from that of patients with lower fibrocyte levels, regardless of disease state. Peripheral blood from patients with IPF (n=16), NSIP (n=7), and age-matched healthy controls (n=15) was collected, their peripheral blood mononuclear cells (PBMCs) isolated by Ficoll separation, and their plasma stored for proteomic analysis. PBMCs and lung tissue digests from patients with fibrotic lung disease (n=9) or normal controls (n=3) were then co-stained for intracellular pro-Collagen I and CD45. Plasma underwent multi-analyte ELISA for a battery of immunologic targets. We found that patients with IPF had elevated fibrocytes as percentage of PBMCs (2.74±2.12%) when compared to NSIP (0.88±0.43%) and healthy controls (0.94±0.84%), as measured by flow cytometry for CD45 and pro-Collagen I co-expression (p \u3c 0.05 NSIP vs. IPF). Furthermore, within the IPF group, fibrocyte levels varied with disease severity (p \u3c 0.05). Interestingly, while lung tissue from patients with active fibrosing pulmonary processes contained elevated fibrocyte levels (3.97±2.7%) when compared with normal human lung tissue (1.04±0.43%, p=0.11), there was no difference between IPF and non-IPF pathology. Lastly, plasma from patients with higher fibrocytes as percentages of PBMCs revealed distinct immune mediator patterns. Specifically, patients with elevated fibrocytes had higher plasma levels of IL-18, IL-8, IL-10, β2-microglobulin, ICAM-1, and TIMP-1 (p \u3c 0.05). No previous study has compared fibrocyte levels in patients with IPF and NSIP. These data suggest there is a relationship between circulating fibrocytes and development of IPF. Moreover, patients with more severe IPF disease had higher levels of circulating fibrocytes, suggesting that they may be a biomarker of both disease state and severity. In addition, lungs of patients with both IPF and non-IPF fibrotic lung disease contained more fibrocytes than healthy lungs, suggesting a broader role for this cell type in the pathogenesis of ILD than previously hypothesized. Lastly, proteomic analysis suggests that elevated fibrocytes are associated with a distinct immunologic profile, but these results do not correlate with an expected dichotomy of profibrotic TH2 versus TH1 immune profiles. These findings advance our understanding of fibrocytes as they relate to fibrotic lung disease and suggest novel avenues for future investigation

Acute myocardial infarction secondary to mucormycosis after lung transplantation

We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death