Increased Levels of Hyaluronic Acid in Bronchoalveolar Lavage from Patients with Interstitial Lung Diseases, Relationship with Lung Function and Inflammatory Cells Recruitment
Author(s)
Glenda Ernst*,
Jancic Carolina,
Auteri Santiago,
Rodriguez Moncalvo Juan,
Galíndez Fernando,
Grynblat Pedro,
E. Hajos Silvia
Affiliation(s)
Respiratory Rehabilitation Hospital María Ferrer, Buenos Aires, Argentina. National Academy of Medicine, IMEX-CONICET, Buenos Aires, Argentina. Faculty of Pharmacy and Biochemistry, Immunology, IDEHU, UBA-CONICET, Buenos Aires, Argentina.
Respiratory Rehabilitation Hospital María Ferrer, Buenos Aires, Argentina. National Academy of Medicine, IMEX-CONICET, Buenos Aires, Argentina. Faculty of Pharmacy and Biochemistry, Immunology, IDEHU, UBA-CONICET, Buenos Aires, Argentina.
ABSTRACT
Purpose: Interstitial Lung Diseases (ILD) are characterized by inflammation and fibrosis. It described the role of hyaluronic acid (HA) as an immune-regulator. It is not known if HA contributes to the recruitment of inflammatory cells associated with ILD. If this hypothesis was correct, then concentrations of HA in bronchoalveolar lavage (BAL) should correlate with the severity of ILD. Methods: We collected BAL from 22 ILD patients and 15 control subjects. We determined HA and cytokine levels by ELISA. In vitro chemotaxis assays were performed by using a transwell system. Results: We found that ILD patients showed a significant increase in HA, IL-6 levels and the amount of cells in BAL compared to control subjects. We detected a significant positive correlation between HA and IL-6 levels (r = 0.53 and p < 0.001) and an inverse relationship between HA levels and diffusion capacity (r = -0.59, p < 0.01). In vitro, HA induced migration of macrophages and monocytes through a CD44-dependent process. BAL from patients with ILD stimulated macro-phage migration and this was abrogated by hyaluronidase. Conclusions: Our results support the hypothesis that HA contributes to the recruitment of monocytes towards the alveolar space, leading to exacerbation of lung inflammation in ILD patients.
Purpose: Interstitial Lung Diseases (ILD) are characterized by inflammation and fibrosis. It described the role of hyaluronic acid (HA) as an immune-regulator. It is not known if HA contributes to the recruitment of inflammatory cells associated with ILD. If this hypothesis was correct, then concentrations of HA in bronchoalveolar lavage (BAL) should correlate with the severity of ILD. Methods: We collected BAL from 22 ILD patients and 15 control subjects. We determined HA and cytokine levels by ELISA. In vitro chemotaxis assays were performed by using a transwell system. Results: We found that ILD patients showed a significant increase in HA, IL-6 levels and the amount of cells in BAL compared to control subjects. We detected a significant positive correlation between HA and IL-6 levels (r = 0.53 and p < 0.001) and an inverse relationship between HA levels and diffusion capacity (r = -0.59, p < 0.01). In vitro, HA induced migration of macrophages and monocytes through a CD44-dependent process. BAL from patients with ILD stimulated macro-phage migration and this was abrogated by hyaluronidase. Conclusions: Our results support the hypothesis that HA contributes to the recruitment of monocytes towards the alveolar space, leading to exacerbation of lung inflammation in ILD patients.
Cite this paper
Ernst, G. , Carolina, J. , Santiago, A. , Juan, R. , Fernando, G. , Pedro, G. and Silvia, E. (2014) Increased Levels of Hyaluronic Acid in Bronchoalveolar Lavage from Patients with Interstitial Lung Diseases, Relationship with Lung Function and Inflammatory Cells Recruitment. Modern Research in Inflammation, 3, 27-36. doi: 10.4236/mri.2014.32004.
Ernst, G. , Carolina, J. , Santiago, A. , Juan, R. , Fernando, G. , Pedro, G. and Silvia, E. (2014) Increased Levels of Hyaluronic Acid in Bronchoalveolar Lavage from Patients with Interstitial Lung Diseases, Relationship with Lung Function and Inflammatory Cells Recruitment. Modern Research in Inflammation, 3, 27-36. doi: 10.4236/mri.2014.32004.
References
[1] King Jr., T.E. (2005) Clinical Advances in the Diagnosis and Therapy of the Interstitial Lung Diseases. American Journal of Respiratory and Critical Care Medicine, 172, 268-279.
http://dx.doi.org/10.1164/rccm.200503-483OE [2] Kim, R. and Meyer, K.C. (2008) Therapies for Interstitial Lung Disease: Past, Present and Future. Therapeutic Advances in Respiratory Disease, 2, 319-338.
http://dx.doi.org/10.1177/1753465808096948 [3] Nathan, S.D., Shlobin, O.A., Weir, N., Ahmad, S., Kaldjob, J.M., Battle, E., Sheridan, M.J. and du Bois, R.M. (2011) Long-Term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the New Millennium. Chest, 141, 221-229. http://dx.doi.org/10.1378/chest.10-2572 [4] Selman, M., King, T.E., Pardo, A., American Thoracic Society, European Respiratory Society and American College of Chest Physicians (2001) Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy. Annals of Internal Medicine, 134, 136-151. http://dx.doi.org/10.7326/0003-4819-134-2-200101160-00015 [5] Strieter, R.M. (2005) Pathogenesis and Natural History of Usual Interstitial Pneumonia: The Whole Story or the Last Chapter of a Long Novel. Chest, 128, 526S-532S. http://dx.doi.org/10.1378/ chest.128.5_suppl_1.526S [6] Vasakova, M., Sterclova, M., Kolesar, L., Slavcev, A., Pohunek, P., Sulc, J., Skibova, J. and Striz, I. (2009) Bronchoal- veolar Lavage Fluid Cellular Characteristics, Functional Parameters and Cytokine and Chemokine Levels in Interstitial Lung Diseases. Scandinavian Journal of Immunology, 69, 268-274. http://dx.doi.org/10.1111/j.1365-3083.2008.02222.x [7] Jiang, D., Liang, J. and Noble, P.W. (2011) Hyaluronan as an Immune Regulator in Human Diseases. Physiological Reviews, 91, 221-264. http://dx.doi.org/10.1152/physrev.00052.2009 [8] Hällgren, R., Samuelsson, T., Laurent, T.C. and Modig, J. (1989) Accumulation of Hyaluronan (Hyaluronic Acid) in the Lung in Adult Respiratory Distress Syndrome. The American Review of Respiratory Disease, 139, 682-687. http://dx.doi.org/10.1164/ajrccm/139.3.682 [9] Bjermer, L., Lundgren, R. and Hällgren, R. (1989) Hyaluronan and Type III Procollagen Peptide Concentrations in Bronchoalveolar Lavage Fluid in Idiopathic Pulmonary Fibrosis. Thorax, 44, 126-131. http://dx.doi.org/10.1136/thx.44.2.126 [10] Bjermer, L., Eklund, A. and Blaschke, E. (1991) Bronchoalveolar Lavage Fibronectin in Patients with Sarcoidosis: Correlation to Hyaluronan and Disease Activity. European Respiratory Journal, 4, 965-971. [11] Noble, P.W. and Jiang, D. (2006) Matrix Regulation of Lung Injury, Inflammation, and Repair: The Role of Innate Immunity. Proceedings of the American Thoracic Society, 3, 401-404.
http://dx.doi.org/10.1513/pats.200604-097AW [12] Taylor, K.R., Trowbridge, J.M., Rudisill, J.A., Termeer, C.C., Simon, J.C. and Gallo R.L. (2004) Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4. The Journal of Biological Chemistry, 279, 17079-17084. http://dx.doi.org/10.1074/jbc.M310859200 [13] Lesley, J. and Hyman Rand Kincade, P.W. (1993) CD44 and Its Interaction with Extracellular Matrix. Advanced Immunology, 54, 271-335. http://dx.doi.org/10.1016/S0065-2776(08)60537-4 [14] Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G.D., et al. (2005) Regulation of Lung Injury and Repair by Toll-Like Receptors and Hyaluronan. Nature Medicine, 11, 1173-1179. http://dx.doi.org/10.1038/nm1315 [15] Kuipers, M.T., van der Poll, T., Schultz, M.J. and Wieland, C.W. (2011) Bench-to-Bedside Review: Damage-Associated Molecular Patterns in the Onset of Ventilator-Induced Lung Injury. Critical Care, 15, 235-246. http://dx.doi.org/10.1186/cc10437 [16] American Thoracic Society, European Respiratory Society (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine, 165, 277-304. http://dx.doi.org/10.1164/ajrccm.165.2.ats01 [17] Travis, W.D., Costabel, U., Hansell, D.M., King Jr., T.E., Lynch, D.A. and Nicholson, A.G. (2013) An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine, 188, 733-748. http://dx.doi.org/10.1164/rccm. 201308-1483ST [18] Meyer, K.C., Raghu, G., Baughman, R.P., Brown, K.K., Costabel, U., du Bois, R.M., et al. (2012) An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease. American Journal of Respiratory and Critical Care Medicine, 185, 1004-1014. http://dx.doi.org/10.1164/rccm.201202-0320ST [19] Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A. and Crapo, R. (2005) Standardisation of Spirometry. European Respiratory Journal, 26,319-338. http://dx.doi.org/10.1183/ 09031936.05.00034805 [20] Macintyre, N., Crapo, R.O., Viegi, G., Johnson, D.C., van der Grinten, C.P., Brusasco, V. and Burgos, F. (2005) Standardisation of the Single-Breath Determination of Carbon Monoxide Uptake in the Lung. European Respiratory Journal, 26, 720-735. http://dx.doi.org/10.1183/09031936.05.00034905 [21] Cordo Russo, R.I., Ernst, G., Lompardía, S., Blanco, G., álvarez, é., Garcia, M.G. and Hajos, S. (2012) Increased Hyaluronan Levels and Decreased Dendritic Cell Activation Are Associated with Tumor Invasion in Murine Lymphoma Cell Lines. Immunobiology, 217, 842-850. http://dx.doi.org/10.1016/ j.imbio.2011.12.006 [22] Jancic, C.C., Cabrini, M., Gabelloni, M.L., Rodríguez, Rodrigues, C., Salamone, G., Trevani, A.S. and Geffner, J. (2012) Low Extracellular pH Stimulates the Production of IL-1β by Human Monocytes. Cytokine, 57, 258-268. http://dx.doi.org/10.1016/j.cyto.2011.11.013 [23] Ernst, G., Lompardía, S., Cordo Russo, R., Gentilini, V., Venturiello, S., Galíndez, F., Grynblat, P. and Hajos, S.E. (2012) Corticosteroid Administration Reduces the Concentration of Hyaluronan in Bronchoalveolar Lavage in a Murine Model of Eosinophilic Airway Inflammation. Inflammation Research, 61, 1309-1317. http://dx.doi.org/10.1007/s00011-012-0530-y [24] Collins, S.L., Black, K.E., Yee, C.-L., Ahn, Y.-H., Cole, P.A., Powell, J.D. and Horton, M.R. (2011) Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor. American Journal of Respiratory Cell and Molecular Biology, 45, 675-683.
http://dx.doi.org/10.1165/rcmb.2010-0387OC [25] Scheibner, K.A., Lutz, M.A., Boodoo, S., Fenton, M.J., Powell, J.D. and Horton, M.R. (2006) Hyaluronan Fragments Act as an Endogenous Danger Signal by Engaging TLR2. The Journal of Immunology, 177, 1272-1281. [26] Powell, J.D. and Horton, M.R. (2005) Threat Matrix: Low-Molecular-Weight Hyaluronan (HA) as a Danger Signal. Immunologic Research, 31, 207-218. http://dx.doi.org/10.1385/IR:31:3:207 [27] Bjermer, L., Engström-Laurent, A., Lundgren, R., Rosenhall, L. and Hällgren, R. (1987) Hyaluronate and Type III Procollagen Peptide Concentrations in Bronchoalveolar Lavage Fluid as Markers of Disease Activity in Farmer’s Lung. British Medical Journal (Clinical Research Ed.), 295, 803-806. http://dx.doi.org/10.1136/bmj.295.6602.803 [28] Cormier, Y,. Laviolette, M., Cantin, A., Tremblay, G.M. and Bégin, R. (1993) Fibrogenic Activities in Bronchoalveolar Lavage Fluid of Farmer’s Lung. Chest, 104, 1038-1042. http://dx.doi.org/10.1378/ chest.104.4.1038 [29] Cantin, A.M., Larivée, P., Martel, M. and Bégin, R. (1992) Hyaluronan (Hyaluronic Acid) in Lung Lavage of Asbestos-Exposed Humans and Sheep. Lung, 170, 211-220. http://dx.doi.org/10.1007/BF 00174118 [30] Milman, N., Kristensen, M.S. and Bentsen, K. (1995) Hyaluronan and Procollagen Type III Aminoterminal Peptide in Serum and Bronchoalveolar Lavage Fluid from Patients with Pulmonary Fibrosis. APMIS, 103, 749-754. http://dx.doi.org/10.1111/j.1699-0463.1995.tb01433.x [31] Mikecz, K., Brennan, F.R., Kim, J.H. and Glant, T.T. (1995) Anti-CD44 Treatment Abrogates Tissue Oedema and Leukocyte Infiltration in Murine Arthritis. Nature Medicine, 1, 558-563.
http://dx.doi.org/10.1038/nm0695-558 [32] Li, Y., Jiang, D., Liang, J., Meltzer, E.B., Gray, A., Miura, R., Wogensen, L., Yamaguchi, Y. and Noble, P.W. (2011) Severe Lung Fibrosis Requires an Invasive Fibroblast Phenotype Regulated by Hyaluronan and CD44. The Journal of Experimental Medicine, 208, 1459-1471.
http://dx.doi.org/10.1084/jem.20102510
[1] King Jr., T.E. (2005) Clinical Advances in the Diagnosis and Therapy of the Interstitial Lung Diseases. American Journal of Respiratory and Critical Care Medicine, 172, 268-279.
http://dx.doi.org/10.1164/rccm.200503-483OE [2] Kim, R. and Meyer, K.C. (2008) Therapies for Interstitial Lung Disease: Past, Present and Future. Therapeutic Advances in Respiratory Disease, 2, 319-338.
http://dx.doi.org/10.1177/1753465808096948 [3] Nathan, S.D., Shlobin, O.A., Weir, N., Ahmad, S., Kaldjob, J.M., Battle, E., Sheridan, M.J. and du Bois, R.M. (2011) Long-Term Course and Prognosis of Idiopathic Pulmonary Fibrosis in the New Millennium. Chest, 141, 221-229. http://dx.doi.org/10.1378/chest.10-2572 [4] Selman, M., King, T.E., Pardo, A., American Thoracic Society, European Respiratory Society and American College of Chest Physicians (2001) Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy. Annals of Internal Medicine, 134, 136-151. http://dx.doi.org/10.7326/0003-4819-134-2-200101160-00015 [5] Strieter, R.M. (2005) Pathogenesis and Natural History of Usual Interstitial Pneumonia: The Whole Story or the Last Chapter of a Long Novel. Chest, 128, 526S-532S. http://dx.doi.org/10.1378/ chest.128.5_suppl_1.526S [6] Vasakova, M., Sterclova, M., Kolesar, L., Slavcev, A., Pohunek, P., Sulc, J., Skibova, J. and Striz, I. (2009) Bronchoal- veolar Lavage Fluid Cellular Characteristics, Functional Parameters and Cytokine and Chemokine Levels in Interstitial Lung Diseases. Scandinavian Journal of Immunology, 69, 268-274. http://dx.doi.org/10.1111/j.1365-3083.2008.02222.x [7] Jiang, D., Liang, J. and Noble, P.W. (2011) Hyaluronan as an Immune Regulator in Human Diseases. Physiological Reviews, 91, 221-264. http://dx.doi.org/10.1152/physrev.00052.2009 [8] Hällgren, R., Samuelsson, T., Laurent, T.C. and Modig, J. (1989) Accumulation of Hyaluronan (Hyaluronic Acid) in the Lung in Adult Respiratory Distress Syndrome. The American Review of Respiratory Disease, 139, 682-687. http://dx.doi.org/10.1164/ajrccm/139.3.682 [9] Bjermer, L., Lundgren, R. and Hällgren, R. (1989) Hyaluronan and Type III Procollagen Peptide Concentrations in Bronchoalveolar Lavage Fluid in Idiopathic Pulmonary Fibrosis. Thorax, 44, 126-131. http://dx.doi.org/10.1136/thx.44.2.126 [10] Bjermer, L., Eklund, A. and Blaschke, E. (1991) Bronchoalveolar Lavage Fibronectin in Patients with Sarcoidosis: Correlation to Hyaluronan and Disease Activity. European Respiratory Journal, 4, 965-971. [11] Noble, P.W. and Jiang, D. (2006) Matrix Regulation of Lung Injury, Inflammation, and Repair: The Role of Innate Immunity. Proceedings of the American Thoracic Society, 3, 401-404.
http://dx.doi.org/10.1513/pats.200604-097AW [12] Taylor, K.R., Trowbridge, J.M., Rudisill, J.A., Termeer, C.C., Simon, J.C. and Gallo R.L. (2004) Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4. The Journal of Biological Chemistry, 279, 17079-17084. http://dx.doi.org/10.1074/jbc.M310859200 [13] Lesley, J. and Hyman Rand Kincade, P.W. (1993) CD44 and Its Interaction with Extracellular Matrix. Advanced Immunology, 54, 271-335. http://dx.doi.org/10.1016/S0065-2776(08)60537-4 [14] Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G.D., et al. (2005) Regulation of Lung Injury and Repair by Toll-Like Receptors and Hyaluronan. Nature Medicine, 11, 1173-1179. http://dx.doi.org/10.1038/nm1315 [15] Kuipers, M.T., van der Poll, T., Schultz, M.J. and Wieland, C.W. (2011) Bench-to-Bedside Review: Damage-Associated Molecular Patterns in the Onset of Ventilator-Induced Lung Injury. Critical Care, 15, 235-246. http://dx.doi.org/10.1186/cc10437 [16] American Thoracic Society, European Respiratory Society (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine, 165, 277-304. http://dx.doi.org/10.1164/ajrccm.165.2.ats01 [17] Travis, W.D., Costabel, U., Hansell, D.M., King Jr., T.E., Lynch, D.A. and Nicholson, A.G. (2013) An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. American Journal of Respiratory and Critical Care Medicine, 188, 733-748. http://dx.doi.org/10.1164/rccm. 201308-1483ST [18] Meyer, K.C., Raghu, G., Baughman, R.P., Brown, K.K., Costabel, U., du Bois, R.M., et al. (2012) An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease. American Journal of Respiratory and Critical Care Medicine, 185, 1004-1014. http://dx.doi.org/10.1164/rccm.201202-0320ST [19] Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A. and Crapo, R. (2005) Standardisation of Spirometry. European Respiratory Journal, 26,319-338. http://dx.doi.org/10.1183/ 09031936.05.00034805 [20] Macintyre, N., Crapo, R.O., Viegi, G., Johnson, D.C., van der Grinten, C.P., Brusasco, V. and Burgos, F. (2005) Standardisation of the Single-Breath Determination of Carbon Monoxide Uptake in the Lung. European Respiratory Journal, 26, 720-735. http://dx.doi.org/10.1183/09031936.05.00034905 [21] Cordo Russo, R.I., Ernst, G., Lompardía, S., Blanco, G., álvarez, é., Garcia, M.G. and Hajos, S. (2012) Increased Hyaluronan Levels and Decreased Dendritic Cell Activation Are Associated with Tumor Invasion in Murine Lymphoma Cell Lines. Immunobiology, 217, 842-850. http://dx.doi.org/10.1016/ j.imbio.2011.12.006 [22] Jancic, C.C., Cabrini, M., Gabelloni, M.L., Rodríguez, Rodrigues, C., Salamone, G., Trevani, A.S. and Geffner, J. (2012) Low Extracellular pH Stimulates the Production of IL-1β by Human Monocytes. Cytokine, 57, 258-268. http://dx.doi.org/10.1016/j.cyto.2011.11.013 [23] Ernst, G., Lompardía, S., Cordo Russo, R., Gentilini, V., Venturiello, S., Galíndez, F., Grynblat, P. and Hajos, S.E. (2012) Corticosteroid Administration Reduces the Concentration of Hyaluronan in Bronchoalveolar Lavage in a Murine Model of Eosinophilic Airway Inflammation. Inflammation Research, 61, 1309-1317. http://dx.doi.org/10.1007/s00011-012-0530-y [24] Collins, S.L., Black, K.E., Yee, C.-L., Ahn, Y.-H., Cole, P.A., Powell, J.D. and Horton, M.R. (2011) Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor. American Journal of Respiratory Cell and Molecular Biology, 45, 675-683.
http://dx.doi.org/10.1165/rcmb.2010-0387OC [25] Scheibner, K.A., Lutz, M.A., Boodoo, S., Fenton, M.J., Powell, J.D. and Horton, M.R. (2006) Hyaluronan Fragments Act as an Endogenous Danger Signal by Engaging TLR2. The Journal of Immunology, 177, 1272-1281. [26] Powell, J.D. and Horton, M.R. (2005) Threat Matrix: Low-Molecular-Weight Hyaluronan (HA) as a Danger Signal. Immunologic Research, 31, 207-218. http://dx.doi.org/10.1385/IR:31:3:207 [27] Bjermer, L., Engström-Laurent, A., Lundgren, R., Rosenhall, L. and Hällgren, R. (1987) Hyaluronate and Type III Procollagen Peptide Concentrations in Bronchoalveolar Lavage Fluid as Markers of Disease Activity in Farmer’s Lung. British Medical Journal (Clinical Research Ed.), 295, 803-806. http://dx.doi.org/10.1136/bmj.295.6602.803 [28] Cormier, Y,. Laviolette, M., Cantin, A., Tremblay, G.M. and Bégin, R. (1993) Fibrogenic Activities in Bronchoalveolar Lavage Fluid of Farmer’s Lung. Chest, 104, 1038-1042. http://dx.doi.org/10.1378/ chest.104.4.1038 [29] Cantin, A.M., Larivée, P., Martel, M. and Bégin, R. (1992) Hyaluronan (Hyaluronic Acid) in Lung Lavage of Asbestos-Exposed Humans and Sheep. Lung, 170, 211-220. http://dx.doi.org/10.1007/BF 00174118 [30] Milman, N., Kristensen, M.S. and Bentsen, K. (1995) Hyaluronan and Procollagen Type III Aminoterminal Peptide in Serum and Bronchoalveolar Lavage Fluid from Patients with Pulmonary Fibrosis. APMIS, 103, 749-754. http://dx.doi.org/10.1111/j.1699-0463.1995.tb01433.x [31] Mikecz, K., Brennan, F.R., Kim, J.H. and Glant, T.T. (1995) Anti-CD44 Treatment Abrogates Tissue Oedema and Leukocyte Infiltration in Murine Arthritis. Nature Medicine, 1, 558-563.
http://dx.doi.org/10.1038/nm0695-558 [32] Li, Y., Jiang, D., Liang, J., Meltzer, E.B., Gray, A., Miura, R., Wogensen, L., Yamaguchi, Y. and Noble, P.W. (2011) Severe Lung Fibrosis Requires an Invasive Fibroblast Phenotype Regulated by Hyaluronan and CD44. The Journal of Experimental Medicine, 208, 1459-1471.
http://dx.doi.org/10.1084/jem.20102510