Endoplasmic Reticulum Stress Induces Hyaluronan Deposition and Leukocyte Adhesion

There is mounting evidence that perturbations in endoplasmic reticulum (ER) function play a key role in the pathogenesis of a broad range of diseases. We have examined the ability of ER stress to modulate leukocyte binding to colonic and aortic smooth muscle cells. In vitro, control smooth muscle cells bind few leukocytes, but treatment with compounds that induce ER stress, including tunicamycin, A23187, and thapsigargin, promotes leukocyte binding. Likewise, dextran sulfate, another agent capable of inducing ER stress and promoting inflammation in vivo, strongly induces leukocyte adhesion. The bound leukocytes are released by hyaluronidase treatment, indicating a critical role for hyaluronan-containing structures in mediating leukocyte binding. Affinity histochemistry demonstrated that hyaluronan accumulates and is present in cable-like structures in the treated, but not the untreated, cultures and that these structures serve as attachment sites for leukocytes. Hyaluronan-rich regions of both murine and human inflamed colon contain numerous cells that stain intensely for ER-resident chaperones containing the KDEL sequence, demonstrating a relationship between ER stress and hyaluronan deposition in vivo. These results indicate that ER stress may contribute to chronic inflammation by forming a hyaluronan-rich extracellular matrix that is conducive to leukocyte binding. There is mounting evidence that perturbations in endoplasmic reticulum (ER) function play a key role in the pathogenesis of a broad range of diseases. We have examined the ability of ER stress to modulate leukocyte binding to colonic and aortic smooth muscle cells. In vitro, control smooth muscle cells bind few leukocytes, but treatment with compounds that induce ER stress, including tunicamycin, A23187, and thapsigargin, promotes leukocyte binding. Likewise, dextran sulfate, another agent capable of inducing ER stress and promoting inflammation in vivo, strongly induces leukocyte adhesion. The bound leukocytes are released by hyaluronidase treatment, indicating a critical role for hyaluronan-containing structures in mediating leukocyte binding. Affinity histochemistry demonstrated that hyaluronan accumulates and is present in cable-like structures in the treated, but not the untreated, cultures and that these structures serve as attachment sites for leukocytes. Hyaluronan-rich regions of both murine and human inflamed colon contain numerous cells that stain intensely for ER-resident chaperones containing the KDEL sequence, demonstrating a relationship between ER stress and hyaluronan deposition in vivo. These results indicate that ER stress may contribute to chronic inflammation by forming a hyaluronan-rich extracellular matrix that is conducive to leukocyte binding. The pathogenesis of chronic inflammatory conditions such as inflammatory bowel disease, atherosclerosis, and asthma is not well understood. During the immune response, leukocytes infiltrate and remain resident within the affected tissue, many in close proximity to smooth muscle cells (SMCs). 1The abbreviations used are: SMCsmooth muscle cellERendoplasmic reticulumHAhyaluronanIαIinter-α-trypsin inhibitorFBSfetal bovine serumPBSphosphate-buffered saline. Once the leukocytes leave the vasculature and enter the inflamed tissue, they encounter a myriad of extracellular matrix and cell surface components. However, it is not clear with which components the leukocytes interact nor what regulates leukocyte migration and adhesion within the inflamed tissue (1de Fougerolles A.R. Chi-Rosso G. Bajardi A. Gotwals P. Green C.D. Koteliansky V.E. Immunity. 2000; 13: 749-758Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 2Vaday G.G. Franitza S. Schor H. Hecht I. Brill A. Cahalon L. Hershkoviz R. Lider O. J. Leukocyte Biol. 2001; 69: 885-892PubMed Google Scholar, 3Shimizu Y. Shaw S. FASEB J. 1991; 5: 2292-2299Crossref PubMed Scopus (309) Google Scholar). Even less is known about the factors that determine the ultimate destination of migrating leukocytes. smooth muscle cell endoplasmic reticulum hyaluronan inter-α-trypsin inhibitor fetal bovine serum phosphate-buffered saline. Hyaluronan (HA) is a linear glycosaminoglycan composed of alternating units of β1,3-d-glucuronic acid and β1,4-N-acetyld-glucosamine (4Fraser J.R. Laurent T.C. Laurent U.B. J. Intern. Med. 1997; 242: 27-33Crossref PubMed Scopus (1483) Google Scholar). A family of hyaluronan synthase enzymes (Has-1, Has-2, and Has-3) (5Weigel P.H. Hascall V.C. Tammi M. J. Biol. Chem. 1997; 272: 13997-14000Abstract Full Text Full Text PDF PubMed Scopus (624) Google Scholar) catalyze the formation of HA at the cell surface, and during synthesis, the nascent chain is extruded into the extracellular space. HA can associate with other extracellular matrix components and become incorporated into the matrix via high affinity interactions (4Fraser J.R. Laurent T.C. Laurent U.B. J. Intern. Med. 1997; 242: 27-33Crossref PubMed Scopus (1483) Google Scholar), or it can remain associated with the cell surface via several receptors, including specific forms of CD44 (4Fraser J.R. Laurent T.C. Laurent U.B. J. Intern. Med. 1997; 242: 27-33Crossref PubMed Scopus (1483) Google Scholar). HA has several functions relative to inflammation, and the interactions of leukocytes with HA may be involved in their capture and retention within areas of inflammation. Hyaluronan accumulates in the extracellular matrix and in serum in many inflammatory states, and often the serum level correlates with the degree of inflammation (6Gerdin B. Hallgren R. J. Intern. Med. 1997; 242: 49-55Crossref PubMed Scopus (111) Google Scholar, 7Laurent T.C. Laurent U.B. Fraser J.R. Ann. Med. 1996; 28: 241-253Crossref PubMed Scopus (167) Google Scholar). Several studies have demonstrated that activated leukocytes can bind to endothelial cell HA (8DeGrendele H.C. Kosfiszer M. Estess P. Siegelman M.H. J. Immunol. 1997; 159: 2549-2553PubMed Google Scholar, 9DeGrendele H.C. Estess P. Siegelman M.H. Science. 1997; 278: 672-675Crossref PubMed Scopus (478) Google Scholar, 10Siegelman M.H. DeGrendele H.C. Estess P. J. Leukocyte Biol. 1999; 66: 315-321Crossref PubMed Scopus (180) Google Scholar, 11Estess P. Nandi A. Mohamadzadeh M. Siegelman M.H. J. Exp. Med. 1999; 190: 9-19Crossref PubMed Scopus (66) Google Scholar, 12Nandi A. Estess P. Siegelman M.H. J. Biol. Chem. 2000; 275: 14939-14948Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar), and we recently demonstrated that leukocytes can bind to virally infected SMCs via novel structures formed by HA (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 14de la Motte C.A. Hascall V.C. Drazba J. Bandyopadhyay S.K. Strong S.A. Am. J. Pathol. 2003; 163: 121-133Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). The interactions of leukocytes with HA produced by SMCs may be important for modulating and perpetuating the inflammatory response; however, little is known about what factors regulate SMC production of the leukocyte-binding structures of HA. Identification of mediators that contribute to the production of HA as well as factors that can inhibit its accumulation may lead to the development of novel therapeutic targets and improved therapies for patients with chronic inflammatory conditions. The endoplasmic reticulum (ER) is a dynamic membranous organelle with diverse functions including 1) protein synthesis, modification, folding, and subunit assembly; 2) steroid synthesis; 3) lipid synthesis; 4) glycogen production; 5) sequestration of calcium; and 6) maintenance of calcium homeostasis. Many infectious agents, environmental toxins, and adverse metabolic conditions interfere with ER function and homeostasis, thereby inducing ER stress (15Aridor M. Balch W.E. Nat. Med. 1999; 5: 745-751Crossref PubMed Scopus (256) Google Scholar, 16Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1097) Google Scholar, 17Pahl H.L. Physiol. Rev. 1999; 79: 683-701Crossref PubMed Scopus (307) Google Scholar, 18Ron D. J. Clin. Invest. 2002; 110: 1383-1388Crossref PubMed Scopus (739) Google Scholar, 19Lee A.S. Trends Biochem. Sci. 2001; 26: 504-510Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar). Cells elicit the ER stress response/unfolded protein response in an attempt to restore homeostasis by eliminating the discrepancy between ER capacity and demand (15Aridor M. Balch W.E. Nat. Med. 1999; 5: 745-751Crossref PubMed Scopus (256) Google Scholar, 16Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1097) Google Scholar, 17Pahl H.L. Physiol. Rev. 1999; 79: 683-701Crossref PubMed Scopus (307) Google Scholar, 18Ron D. J. Clin. Invest. 2002; 110: 1383-1388Crossref PubMed Scopus (739) Google Scholar, 19Lee A.S. Trends Biochem. Sci. 2001; 26: 504-510Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar). It is not known how the extracellular matrix is affected by ER stress. Bertolotti et al. (20Bertolotti A. Wang X. Novoa I. Jungreis R. Schlessinger K. Cho J.H. West A.B. Ron D. J. Clin. Invest. 2001; 107: 585-593Crossref PubMed Scopus (323) Google Scholar) recently demonstrated that perturbations in ER function that result in ER stress influence the development of dextran sulfate-induced colitis. Knockout mice deficient in IRE1β, a protein that senses and responds to ER stress, are particularly sensitive to the induction of colitis. IRE1β-deficient mice treated with dextran sulfate developed more severe colitis that occurred several days earlier than in their wild type counterparts (20Bertolotti A. Wang X. Novoa I. Jungreis R. Schlessinger K. Cho J.H. West A.B. Ron D. J. Clin. Invest. 2001; 107: 585-593Crossref PubMed Scopus (323) Google Scholar). Interestingly, the IRE1β gene is located in a region of chromosome 16 known to contain gene(s) that modulate susceptibility to inflammatory bowel disease, the IBD1 locus (20Bertolotti A. Wang X. Novoa I. Jungreis R. Schlessinger K. Cho J.H. West A.B. Ron D. J. Clin. Invest. 2001; 107: 585-593Crossref PubMed Scopus (323) Google Scholar). How ER stress is linked to immune dysregulation is not known, but ER stress probably induces the expression of specific genes or activates particular enzymes that promote inflammation. In the current investigation, we demonstrate that agents that induce ER stress within SMCs promote HA deposition and leukocyte adhesion to HA-containing structures. a novel of the and function of the extracellular matrix as a of ER stress. The The dextran sulfate for in studies The the and the inhibitor tissue in with an the and SMCs colon as (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, S.A. Full Text Full Text PDF PubMed Scopus Google Scholar). aortic SMCs as A. Biol. 1997; PubMed Scopus Google Scholar). Cells in with fetal bovine serum and an cells in with and the at in and Leukocyte of leukocyte adhesion to SMCs as (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). SMCs to in and treated with the compounds for to the cells or leukocytes (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar) for at with of The cells with containing and at a of in with and The leukocytes to the SMCs and at for leukocytes by the with containing by the cells with and the of an in a In a of the cells to treated cultures The of cells bound to HA by with bovine hyaluronidase type for to the In the binding of leukocytes to HA by the SMC with hyaluronidase with or a of to the In other the binding of leukocytes to cell adhesion by of the SMCs with a for at to the of leukocytes. The CD44 the cells in these studies to be in the binding as by its to bind to high HA. Affinity and at the of they with at and in and binding with containing or bovine serum with the of and with protein in containing the with containing the and and or The and with mounting containing to the examined with a for The and the protein in as tissue tissue in in and The and examined as for the cells. of the cultures examined for their capacity to the cells with phosphate-buffered the cultures with and the of cells of the to cells treated with compounds and The cells in in for at in in and cells by mice in these and by the sulfate by it to the at a of mice and their in and in with for a at ER Leukocyte in of ER stress colonic SMCs examined by treatment for at with or tunicamycin, a well of ER stress H.L. Physiol. Rev. 1999; 79: 683-701Crossref PubMed Scopus (307) Google Scholar, 19Lee A.S. Trends Biochem. Sci. 2001; 26: 504-510Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar, R.J. 1999; 13: PubMed Scopus Google Scholar). The SMC cultures with cells cell for at to control SMCs bound few but treatment leukocyte adhesion with tunicamycin, in binding The of bound leukocytes with hyaluronidase treatment demonstrating that HA has an role in mediating the Likewise, of the SMCs with hyaluronidase to the of leukocytes their attachment The hyaluronidase the hyaluronidase for with a of and indicating that not for the cells bound to SMCs in the of the control and cells demonstrated that induce ER stress, as by the for ER containing the KDEL retention the deposition of of and numerous HA Many of HA into these but not of the for the and inter-α-trypsin inhibitor demonstrated that the treatment not induce the conditions of cells as with of untreated, control these results demonstrate that treatment of SMCs promotes ER stress, the deposition of and leukocyte adhesion by a HA. in calcium homeostasis induce ER stress. A23187, a calcium and thapsigargin, an inhibitor of the reticulum type are both of ER stress. and they leukocyte adhesion to SMC cultures In stress treatment for nor for and for leukocyte adhesion sulfate, a used in to induce inflammation in a well of strongly adhesion of leukocytes to SMCs adhesion by SMC cultures to dextran sulfate for at treatment the bound and of the cell with hyaluronidase to the of leukocytes leukocyte attachment These results demonstrate that attachment by HA. dextran sulfate treatment strongly the accumulation of HA in the SMC ER a Leukocyte The leukocyte adhesion aortic SMCs treated with dextran sulfate leukocyte adhesion a the containing dextran sulfate and with the SMCs for leukocytes for an days and the dextran sulfate the treated SMC cultures bound and more leukocytes, than SMCs the of the treated SMCs than that of untreated, control SMCs but by the treated SMCs we the of dextran sulfate leukocyte adhesion or in the of dextran SMCs treated with dextran sulfate for a treatment, leukocyte adhesion days of treatment, the for leukocytes to control In the of dextran sulfate, the SMCs for to a of control the the adhesion by as demonstrated by the capacity of hyaluronidase to the bound leukocytes HA protein is for the induction of leukocyte adhesion to SMCs treated with dextran aortic SMCs with for and treated with or both dextran sulfate and for sulfate at promoting leukocyte adhesion in the or the of to induce leukocyte adhesion colonic aortic SMCs of as by its to hyaluronidase of extracellular HA in cultures of aortic SMCs of treatment with dextran sulfate numerous HA-containing a response that protein is to be for HA with the that not the of dextran sulfate leukocyte adhesion. In the deposition of HA of treatment, HA and of treatment, formed The HA in of treatment with dextran sulfate is capable of binding leukocytes of treatment, numerous can be bound to the and by bound with leukocytes are present of treatment, many are present that leukocyte adhesion leukocyte adhesion these and demonstrate that leukocyte adhesion with treatment binding of dextran sulfate treatment, and treatment, and of binding ER with HA in we the between ER stress and HA deposition in vivo. we examined mice treated with dextran sulfate to induce inflammation in the tissue mice treated with dextran sulfate for days for both HA and tissue mice for and of for 6) that at a we examined of human colon for evidence of ER stress and HA deposition in vivo. In inflamed numerous cells intensely for in areas in HA. Likewise, regions with less HA less strongly for These in both and human tissue that ER stress is associated with HA deposition in human colon for ER stress and HA. colon and as for the and Leukocyte the at sites of inflammation is by the expression of specific adhesion the surface of both leukocytes and endothelial cells. A of have demonstrated that activated leukocytes can bind to endothelial HA via the cell surface CD44 both in and in P. Nandi A. Mohamadzadeh M. Siegelman M.H. J. Exp. Med. 1999; 190: 9-19Crossref PubMed Scopus (66) Google Scholar). the adhesion of activated cells to and their are by endothelial HA and the of CD44 by the (8DeGrendele H.C. Kosfiszer M. Estess P. Siegelman M.H. J. Immunol. 1997; 159: 2549-2553PubMed Google Scholar, 9DeGrendele H.C. Estess P. Siegelman M.H. Science. 1997; 278: 672-675Crossref PubMed Scopus (478) Google Scholar, 10Siegelman M.H. DeGrendele H.C. Estess P. J. Leukocyte Biol. 1999; 66: 315-321Crossref PubMed Scopus (180) Google Scholar, 11Estess P. Nandi A. Mohamadzadeh M. Siegelman M.H. J. Exp. Med. 1999; 190: 9-19Crossref PubMed Scopus (66) Google Scholar, 12Nandi A. Estess P. Siegelman M.H. J. Biol. Chem. 2000; 275: 14939-14948Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). of HA the surface of endothelial cells can be by such as and P. Nandi A. Mohamadzadeh M. Siegelman M.H. J. Exp. Med. 1999; 190: 9-19Crossref PubMed Scopus (66) Google Scholar, M. DeGrendele H. H. Estess P. Siegelman M. J. Clin. Invest. PubMed Scopus Google Scholar). However, it is less clear what regulates the migration and adhesion of leukocytes they enter the tissue of inflamed HA accumulates in numerous inflammatory conditions including inflammatory bowel disease, atherosclerosis, and (6Gerdin B. Hallgren R. J. Intern. Med. 1997; 242: 49-55Crossref PubMed Scopus (111) Google Scholar, 7Laurent T.C. Laurent U.B. Fraser J.R. Ann. Med. 1996; 28: 241-253Crossref PubMed Scopus (167) Google Scholar, 14de la Motte C.A. Hascall V.C. Drazba J. Bandyopadhyay S.K. Strong S.A. Am. J. Pathol. 2003; 163: 121-133Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, Tammi J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Clin. Exp. Physiol. 2001; 28: PubMed Scopus Google Scholar, Hallgren R. G. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The accumulation of HA in areas of inflammation that the production of HA by including may play an role in leukocyte adhesion and The that interactions are associated with the of with the of and with leukocyte migration that HA can have a dynamic role in the inflammatory J. R. J. 1997; PubMed Scopus Google Scholar, J. Sci. PubMed Google Scholar, R. R. J. Immunol. 2002; PubMed Scopus Google Scholar). However, little is known factors that modulate the production of HA in inflamed We have that of colonic SMCs with or with a the binding of leukocytes to SMCs (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). of binding a by cell adhesion and a novel by HA (13de la Motte C.A. Hascall V.C. Calabro A. Yen-Lieberman B. Strong S.A. J. Biol. Chem. 1999; 274: 30747-30755Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 14de la Motte C.A. Hascall V.C. Drazba J. Bandyopadhyay S.K. Strong S.A. Am. J. Pathol. 2003; 163: 121-133Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). is the of cell adhesion can induce the deposition of a leukocyte-binding of other factors that regulate the deposition and accumulation of of HA and the of their are A of and conditions induce stress. The of cells to such as ER stress, stress, and serve to restore homeostasis. A of diverse factors may ER stress including of calcium acid and the accumulation of in the ER is by that or in the ER and by to stress with a of R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1097) Google Scholar, 18Ron D. J. Clin. Invest. 2002; 110: 1383-1388Crossref PubMed Scopus (739) Google Scholar, R.J. 1999; 13: PubMed Scopus Google Scholar). In an to restore homeostasis, cells with ER stress by the expression of numerous involved in protein and protein and by protein to the of the is the to demonstrate that ER stress of SMCs induces leukocyte adhesion and that the adhesion an results demonstrate that ER stress, of its promotes the adhesion of leukocytes to The bound leukocytes are by hyaluronidase treatment, demonstrating that HA-containing structures are important in the binding. Likewise, the binding of leukocytes to SMCs is by the cell with hyaluronidase the of leukocytes. the cell for HA with affinity histochemistry that the HA is in cultures and that it accumulates in a cable-like of these contain and which are both known to bind to HA and which we have can with HA in structures la Motte C.A. Hascall V.C. Drazba J. Bandyopadhyay S.K. Strong S.A. Am. J. Pathol. 2003; 163: 121-133Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, la Motte C.A. Hascall V.C. Drazba Strong S.A. Hascall V.C. and Scholar). HA demonstrated the of bound leukocytes with HA-containing structures. is not to other cell such as cells and to ER stress by HA in a capable of binding leukocytes. deposition of HA in cultures is within of treatment, well within the to induce ER stress. The of HA that are in are capable of binding leukocytes. the to into that contain and the of that are present are to bind as many leukocytes as cultures treated for that contain ER stress can induce both HA deposition by SMCs and leukocyte adhesion to SMCs treated with dextran sulfate for their capacity to bind leukocytes control for an In the of dextran sulfate, SMCs for leukocytes for These indicate that the HA can for several days and that the ability to to stress and induce HA is not these are with ER stress an role in chronic inflammation. of protein by not the ability of SMCs to HA structures capable of mediating leukocyte adhesion. These results demonstrate that of hyaluronan is not and indicate that of the of HA may be HA is a glycosaminoglycan it can be in the of protein synthesis, that hyaluronan synthase and its are Interestingly, by HA deposition and leukocyte adhesion. that cells are by protein synthesis, the production of HA is and it is in a that leukocytes. however, such as and stress, not elicit leukocyte binding to The accumulation of HA conditions such as ER stress, of protein synthesis, and is with that HA is to perturbations Hascall V.C. Calabro A. Biochem. PubMed Scopus Google Scholar). in that cells with ER stress or of protein HA into the extracellular in vivo, we examined tissue dextran mice and of human colon to determine regions containing high of of ER stress, are associated with for HA. for and affinity histochemistry for HA demonstrated in numerous cells in regions in HA in inflamed colon both the dextran mice and patients with inflammatory bowel These indicate that HA deposition is associated with ER stress in during inflammation. conditions such as ER stress, treatment, and to an of the cells by a of HA that leukocytes. A of of these conditions is their of protein ER stress results in of D. J. Clin. Invest. 2002; 110: 1383-1388Crossref PubMed Scopus (739) Google Scholar, R.J. 1999; 13: PubMed Scopus Google Biochem. J. PubMed Scopus Google and or treatment strongly induces an inhibitor of J. J. 2000; PubMed Scopus Google Scholar), as well as protein which Rev. 2001; PubMed Scopus Google Scholar). such protein is a be a to cells as We that an HA synthase with as an that cells can conditions that protein The HA that is is in structures that serve as a and promote interactions with leukocytes. as a of specific can lead to protein retention in the ER and ER stress (15Aridor M. Balch W.E. Nat. Med. 1999; 5: 745-751Crossref PubMed Scopus (256) Google Scholar, 16Kaufman R.J. J. Clin. Invest. 2002; 110: 1389-1398Crossref PubMed Scopus (1097) Google Scholar, P. Rev. Google Scholar). that are such as many of of the extracellular the ER may be may be to a of of in type the protein in the forms of P.H. D. The and of Scholar). that are in the of the protein and that interfere with the of the lead to the accumulation of in the ER and to ER stress and the severe of P.H. D. The and of Scholar, P.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P.H. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, and patients with have to more HA than control cells J. PubMed Scopus Google Scholar, A. H. PubMed Scopus Google Scholar, H. H. H. R. PubMed Scopus Google Scholar). studies are to determine the HA in is in the that leukocytes and ER stress is for is another tissue may be A of is aortic Rev. Med. 2000; PubMed Scopus Google Scholar). a role in the development of these L. B. K. H.C. Sci. S. A. 1999; PubMed Scopus Google Scholar), known to contain accumulates in the patients with Rev. Med. 2000; PubMed Scopus Google Scholar). ER stress to the accumulation of in the ER a role in the accumulation of and in the aortic inflammation in patients with that is a of tissue P. of Scholar). The results in high of an acid known to ER stress both in and in S.K. J. J. Biochem. J. PubMed Scopus Google Scholar, S.K. S. J. 1999; PubMed Google Scholar, S. S.K. J. S.K. J. Clin. Invest. 2001; 107: PubMed Scopus Google Scholar). with patients with have an accumulation of P. of Scholar). have chronic P. of Scholar). ER stress may play a role in the pathogenesis of the of of type is by ER in cells type aortic and P.H. Invest. Google Scholar). ER stress may play a role in the accumulation of HA and in the chronic inflammation in tissue and studies are In a novel by which ER stress promotes the of and immune cells by the accumulation of a of other of SMCs and leukocytes is not by but by and infectious with results that the interactions between extracellular matrix and leukocytes a therapeutic We the and in the at the for