Procoagulant, Tissue Factor-Bearing Microparticles in Bronchoalveolar Lavage of Interstitial Lung Disease Patients: An Observational Study

Abstract

Coagulation factor Xa appears involved in the pathogenesis of pulmonary fibrosis. Through its interaction with protease activated receptor-1, this protease signals myofibroblast differentiation in lung fibroblasts. Although fibrogenic stimuli induce factor X synthesis by alveolar cells, the mechanisms of local posttranslational factor X activation are not fully understood. Cell-derived microparticles are submicron vesicles involved in different physiological processes, including blood coagulation; they potentially activate factor X due to the exposure on their outer membrane of both phosphatidylserine and tissue factor. We postulated a role for procoagulant microparticles in the pathogenesis of interstitial lung diseases. Nineteen patients with interstitial lung diseases and 11 controls were studied. All subjects underwent bronchoalveolar lavage; interstitial lung disease patients also underwent pulmonary function tests and high resolution CT scan. Microparticles were enumerated in the bronchoalveolar lavage fluid with a solid-phase assay based on thrombin generation. Microparticles were also tested for tissue factor activity. In vitro shedding of microparticles upon incubation with H2O2 was assessed in the human alveolar cell line, A549 and in normal bronchial epithelial cells. Tissue factor synthesis was quantitated by real-time PCR. Total microparticle number and microparticle-associated tissue factor activity were increased in interstitial lung disease patients compared to controls (84±8 vs. 39±3 nM phosphatidylserine; 293±37 vs. 105±21 arbitrary units of tissue factor activity; mean±SEM; p<.05 for both comparisons). Microparticle-bound tissue factor activity was inversely correlated with lung function as assessed by both diffusion capacity and forced vital capacity (r2 = .27 and .31, respectively; p<.05 for both correlations). Exposure of lung epithelial cells to H2O2 caused an increase in microparticle-bound tissue factor without affecting tissue factor mRNA.Procoagulant microparticles are increased in interstitial lung diseases and correlate with functional impairment. These structures might contribute to the activation of factor X and to the factor Xa-mediated fibrotic response in lung injury.

Cell-derived microparticles and the lung

“…When patients were further divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups, the MP-TF procoagulant activity was significantly higher in the former group. Additionally, a statistically significant negative correlation was found between TF-bearing microparticles and both forced vital capacity and DLCO in IPF patients [49]. In the same study, in vitro assays showed that an oxidative stimulus, namely H 2 O 2 , increased the production of procoagulant microparticles by alveolar epithelial cells in culture [49].…”

“…Additionally, a statistically significant negative correlation was found between TF-bearing microparticles and both forced vital capacity and DLCO in IPF patients [49]. In the same study, in vitro assays showed that an oxidative stimulus, namely H 2 O 2 , increased the production of procoagulant microparticles by alveolar epithelial cells in culture [49]. Local synthesis of coagulation factor X and its activation to factor Xa in the lung has been implicated in the pathogenesis of IPF.…”

“…Based on the role of microparticles in blood coagulation, we investigated their presence in diffuse parenchymal lung disease patients [49]. We showed an increased number of microparticles in the BALF of 19 patients with interstitial lung diseases compared with 11 control subjects.…”

The Clinical Utility of Circulating Microparticles’ Measurement in Heart Failure Patients

“…Mononuclears may generate pro-inflammatory MPs upon activation and apoptosis with a calcium-dependent and p38 mitogen-activated protein kinasedependent mechanisms resulting in impact of cytokines, bacterial products, P-selectin, histamine, catecholamines, angiotensin-II, cigarette smoking [36][37][38][39][40]. Furthermore, mononuclear cell-derived MPs may appear spontaneously beyond obvious cause in physiological state [39,40].…”

Cell Derived Microparticles in Gingival Crevicular Fluid from Periodontitis Patients with Type 2 Diabetes

“…Plasma levels of MPs are altered in rheumatoid arthritis (2), oral cancer (3) and diabetes (4). Although the presence of MPs in saliva, urine, bronchoalveolar lavage and synovial fluid have already been shown (5,6), its detection in gingival crevicular fluid (GCF) still needs to be confirmed.…”