Per quanto riguarda gli esperimenti ex-vivo è possibile trarre le seguenti conclusioni:
ü Le concentrazioni di MP nel BAL sono aumentate nei pazienti affetti da fibrosi polmonare rispetto ai ai pazienti con altre patologie
ü I BAL dei pazienti con fibrosi polmonare presentano livelli significativamente aumentati dell’attività del TF associata alle MP rispetto ai BAL dei pazienti con altre patologie.
ü È presente una correlazione tra entità della compromissione funzionale e concentrazione di MP
ü Nei BAL dei pazienti con fibrosi polmonare esiste una correlazione tra i livelli dell’attività del TF associata alle MP e il grado di compromissione polmonare. ü È ipotizzabile quindi un ruolo delle MP nella patogenesi delle PF come illustrato
nella figura seguente (Fig. 12).
A seguito degli esperimenti in-vitro è possibile trarre le seguenti conclusioni:
ü Le A549 sottoposte a stress ossidativo evidenziano un aumento significativo di MP (misurate come PS) e dell’attività del TF associata alle MP (misurato come attività procoagulante presente nel pellet dopo ultracentrifugazione); tali effetti sono inibiti dalla NAC.
ü Nelle A549 i livelli trascrizionali di mRNA del TF non sono modulati dal trattamento con stress ossidativo.
ü L’aumentato livello dell’attività del TF associata alle MP non è quindi determinato da un aumento della trascrizione genica, ma probabilmente da un aumento del numero di MP esprimenti TF, potenzialmente responsabili dell’attivazione in situ del FX.
Conclusioni finali:
ü Le MP sono state proposte come biomarcatori in diverse condizioni patologiche cardiovascolari incluse alcune cardiopatie e l’ipertensione polmonare. Risultati più recenti suggeriscono un uso di queste strutture come marcatori anche di malattie dell’apparato respiratorio. I nostri dati pongono le basi per un uso delle MP come biomarcatori di IPF.
BIBLIOGRAFIA
- Al-Ismaili, Z., A. Palijan, et al (2011). “Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application.” Pediatr. Nephrol. 26, 29-40 - Amabile, N., C. Heiss, et al. (2009). “Increased CD62e+ endothelial microparticle levels predict poor outcome in pulmonary hypertension patients.” J. Heart Lung Transplant. 28, 1081–1086
- American Thoracic Society/European Respiratory Society (2002). “American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.” Am J Respir Crit Care Med 165: 277–304.
- Ardoin, S. P., J. C. Shanahan, et al. (2007). "The role of microparticles in inflammation and thrombosis." Scand J Immunol 66(2-3): 159-65.
- Bargagli, E., C. Olivieri, et al. (2009). "Oxidative stress in the pathogenesis of diffuse lung diseases: a review." Respir Med 103(9): 1245-56.
- Bargagli, E., F. Penza, et al. (2007). "Analysis of carbonylated proteins in bronchoalveolar lavage of patients with diffuse lung diseases." Lung 185(3): 139-44. - Behr, J., B. Degenkolb, et al. (2002). "Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine." Eur Respir J 19(5): 906-11. - Bernal-Mizrachi, L., W. Jy, et al. (2003). “High levels of circulating endothelial microparticles in patients with acute coronary syndromes.” Am. Heart J.145, 962– 970
- Bernimoulin, M., E.K Waters, et al. (2009). “Differential stimulation of monocytic cells results in distinct populations of microparticles.” J Thromb Haemost 7: 1019– 1028.
- Bilyy, R. O., T. Shkandina, et al. (2012). “Macrophages discriminate glycosylation patternsof apoptotic cell-derived microparticles.” J. Biol. Chem. 287, 496–503 - Boulanger, C. M., A. Scoazec, et al. (2001). "Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction." Circulation 104(22): 2649-52.
- Cantin, A. M., S. L. North, et al. (1987). "Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis." J Clin Invest 79(6): 1665-73.
- Cerri, C., D. Chimenti, et al. (2006). “Monocyte/ macrophage-derived microparticles up-regulate inflammatory mediator synthesis by human airway epithelial cells.” J Immunol 177: 1975–1980.
- Chambers, R.C. and C.J Scotton (2012). "Coagulation cascade proteinases in lung injury and fibrosis." Proc Am Thorac Soc 9(3):96-101.
- Choudhury, A., I. Chung, et al. (2007). “Elevated platelet microparticle levels in nonvalvular atrial fibrillation: relationship to p-selectin and antithrombotic therapy.” Chest 131, 809–815
- Conti, F. Fisiologia Medica.
- Dasgupta, S. K., A. Le, et al (2012). “Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium.” Circulation 125, 1664–1672
- Demedts, M., J. Behr, et al. (2005). “High-dose acetylcysteine in idiopathic pulmonary fibrosis.” N Engl J Med 353: 2229–2242.
- Diehl, P., M. Aleker, et al. (2011). “Increased platelet, leukocyte and endothelial microparticles predict enhanced coagulation and vascular inflammation in pulmonary hypertension.” J. Thromb. Thrombolysis 31, 173–179
- Distler, J. H., L. C. Huber, et al. (2006). "Microparticles as mediators of cellular cross-talk in inflammatory disease." Autoimmunity 39(8): 683-90.
- Dursun, I., H. M. Poyrazoglu, et al. (2009). “The relationship between circulating endothelial microparticles and arterial stiffness and atherosclerosis in children with chronic kidney disease.” Nephrol. Dial. Transplant. 24, 2511–2518
- Esposito, K., M. Ciotola, et al. (2006). “Endothelial microparticles correlate with endothelial dysfunction in obese women.” J. Clin. Endocrinol. Metab. 91, 3676–3679 - Faille, D., F. El-Assaad, et al. (2011). “Endocytosis and intracellular processing of platelet microparticles by brain endothelial cells.” J. Cell. Mol. Med. 16, 1731–1738 - Feng, B., Y. Chen, et al. (2010). “Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus.” Atherosclerosis 208, 264–269
- Gonzalez-Quintero, V. H., J. J. Jimenez, et al. (2003). “Elevated plasma endothelial microparticles in preeclampsia.” Am. J. Obstet. Gynecol. 189, 589–593
- Howland, R., Mycek, J., (2007). Le basi della farmacologia.
Jayachandran, M., R. D. Litwiller, et al. (2009). “Circulating microparticles and endogenous estrogen in newly menopausal women.” Climacteric 12, 177–184
- Jose, RJ., AE. Williams, et al. (2014). “Proteinase-activated receptors in fibroproliferative lung disease.” Thorax 69: 190–192.
- Jung, C., P. Sorensson, et al. (2011). “Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST-elevation myocardial infarction.” Atherosclerosis 221: 226–231.
- Kharitonov, S. A. and P. J. Barnes (2001). "Exhaled markers of inflammation." Curr Opin Allergy Clin Immunol 1(3): 217-24.
- Kinnula, V. L., C. L. Fattman, et al. (2005). "Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy." Am J Respir Crit Care Med 172(4): 417-22.
- Kinnula, V. L., U. A. Hodgson, et al. (2006). "Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia." Histopathology 49(1): 66-74.
- Koiou, E., K. Tziomalos, et al. (2011). “Circulating platelet-derived microparticles are elevated in women with polycystic ovary syndrome diagnosed with the 1990 criteria and correlate with serum testosterone levels.” Eur. J. Endocrinol. 165, 63–68 - Lakari, E., P. Paakko, et al. (2000). "Manganese superoxide dismutase and catalase are coordinately expressed in the alveolar region in chronic interstitial pneumonias and granulomatous diseases of the lung." Am J Respir Crit Care Med 161(2 Pt 1): 615-21.
- Levitzky, M. G. Fisiologia Polmonare.
- Litvack, M. L., M. Post, et al. (2011). “IgM promotes the clearance of small particles and apoptotic microparticles by macrophages.” PLoS ONE 6, e17223 - Mercer P.F., R.H Johns (2009). "Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis." Am J Respir Crit Care Med 179(5):414-25.
- Miller M.R, R. Crapo et al. (2005) "General considerations for lung function testing." Eur Respir J 26: 153–161.
- Minagar, A., W. Jy, et al. (2001). “Elevated plasma endothelial microparticles in multiple sclerosis.” Neurology 56, 1319–1324
- Montuschi, P., G. Ciabattoni, et al. (1998). "8-Isoprostane as a biomarker of oxidative stress in interstitial lung diseases." Am J Respir Crit Care Med 158(5 Pt 1): 1524-7.
- Morel, O., N. Morel, et al. (2005). "The significance of circulating microparticles in physiology, inflammatory and thrombotic diseases." Rev Med Interne 26(10): 791- 801.
- Nielsen, C. T., O. Ostergaard, et al. (2012). “Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation.” Arthritis Rheum. 64, 1227–1236
- Nomura, S., N. Inami, et al. (2009). “The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients.” Platelets 20, 16–22
- Ogawa, F., K. Shimizu, et al. (2006). "Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis." Rheumatology (Oxford) 45(7): 815-8.
- Omoto, S., S. Nomura, et al. (1999). “Significance of platelet-derived microparticles and activated platelets in diabetic nephropathy.” Nephron 81, 271– 277
- Omoto, S., S. Nomura, et al. (2002). “Detection of monocyte-derived microparticles in patients with Type II diabetes mellitus.” Diabetology 45, 550–555 - Owens, Apr. and N. Mackman (2011). “Microparticles in hemostasis and thrombosis.” Circ Res 108: 1284–1297.
- Park, M. S., B. A. Owen, et al. (2012). “Quantification of hypercoagulable state after blunt trauma: Microparticle and thrombin generation are increased relative to injury severity, while standard markers are not.” Surgery 151, 831–836
- Pontieri, R., Frati Patologia generale.
- Porro, C., S. Lepore, et al. (2010). “Isolation and characterization of microparticles in sputum of cystic fibrosis patients.” Respir Res 11: 94–101.
- Press, J. Z., M. Reyes, et al. (2012). “Microparticles from ovarian carcinomas are shed into ascites and promote cell migration.” Int. J. Gynecol. Cancer 22, 546–552 - Psathakis, K., D. Mermigkis, et al. (2006). "Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis." Eur J Clin Invest 36(5): 362-7.
- Raghu, G., H.R Collard, et al. (2011). “An official ATS/ERS/JRS/ ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management.” Am J Respir Crit Care Med 183: 788–824.
- Rank, A., R. Nieuwland, et al. (2012). “Hormone replacement therapy leads to increased plasma levels of platelet derived microparticles in postmenopausal women.” Arch. Gynecol. Obstet. 285, 1035–1041
- Redman, C. W. and I. L. Sargent (2008). "Circulating microparticles in normal pregnancy and pre-eclampsia." Placenta 29 Suppl A: S73-7.
- Robbins, R. A. and M. B. Grisham (1997). "Nitric oxide." Int J Biochem Cell Biol 29(6): 857-60.
- Sadallah, S., C. Eken, et al. (2011) "Ectosomes as modulators of inflammation and immunity." Clin Exp Immunol 163(1): 26-32.
- Satta, N., F. Toti, et al. (1997). “Scott syndrome: an inherited defect of the procoagulant activity of platelets.” Platelets 8, 117–124
- Scotton, C. J., M. A. Krupiczojc, et al. (2009). "Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury." J Clin Invest 119(9): 2550-63.
- Sheremata, W. A., W. Jy, et al. (2006). “Interferon-β1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis.” J. Neuroinflammation 3, 23
- Sinning, J. M., J. Losch, et al. (2011). “Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes.” Eur. Heart J. 32, 2034–2041 - Smalley, D. M., N. E. Sheman, et al. (2008). “Isolation and identification of potential urinary microparticle biomarkers of bladder cancer.” J. Proteome Res. 7, 2088–2096
- Tamagawa-Mineoka, R., N. Katoh, et al. (2010). “Platelet activation in patients with psoriasis: increased plasma levels of platelet-derived microparticles and soluble P-selectin.” J. Am. Acad. Dermatol. 62, 621–626
- Terrisse, A. D., N. Puech, et al.(2010). “Internalization of microparticles by endothelial cells promotes platelet/endothelial cell interaction under flow.” J. Thromb. Haemostasis 8, 2810–2819
- Tiitto, L., R. Kaarteenaho-Wiik, et al. (2003). "Expression of the thioredoxin system in interstitial lung disease." J Pathol 201(3): 363-70.
- Umekita, K., T. Hidaka, et al. (2009). “Leukocytapheresis (LCAP) decreases the level of platelet-derived microparticles (MPs) and increases the level of granulocytes-derived MPs: a possible connection with the effect of LCAP on rheumatoid arthritis.” Mod. Rheumatol. 19, 265–272
- Van Beers, E. J., M.C.L. Schaap, et al. (2009). “Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease.” Haematologica 94, 1513–1519
- Vuorinen, K., S. Ohlmeier, et al. (2008). "Peroxiredoxin II expression and its association with oxidative stress and cell proliferation in human idiopathic pulmonary fibrosis." J Histochem Cytochem 56(10): 951-9.
- Waghray, M., Z. Cui, et al. (2005). "Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts." Faseb J 19(7): 854-6
- Wang, J. M., C. Su, et al. (2009). “Elevated circulating endothelial microparticles and brachial-ankle pulse wave velocity in well-controlled hypertensive patients.” J. Hum. Hypertens. 23, 307–315
- Werner, N., S. Wassmann, et al. (2006). “Circulating CD31+ /annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease.” Arterioscler. Thromb. Vasc. Biol. 26, 112–116
- Willekens, F. L., J.M Werre et al. (2005). “Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors.” Blood 105, 2141 2145
- Yasui, H., E.C.Gabazza, et al. (2001). "Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouse." Am J Respir Crit Care Med 163(7):1660-8.
- Ye, R., C. Ye, et al. (2011). “Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis.” Thromb. Res. 130, 253–258 - Yun, C. H., K. H. Jung, et al. (2010). “Increased circulating endothelial microparticles and carotid atherosclerosis in obstructive sleep apnea.” J. Clin. Neurol. 6, 89–98