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Mast Cells in Rapidly Progressive Glomerulonephritis

TIBOR TÓTH^*, RIA TÓTH-JAKATICS^*, SHIRO JIMI^*, MAKOTO IHARA, HIDENORI URATA and SHIGEO TAKEBAYASHI^*

^* Second Department of Pathology, Fukuoka University, School of Medicine, Fukuoka, Japan.
Department of Internal Medicine, Fukuoka University, School of Medicine, Fukuoka, Japan.

Correspondence to Dr. Tibor Tóth, The Second Department of Pathology, Fukuoka University, School of Medicine, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. Phone: +81-92-801-1011; Fax: +81-92-863-8383; E-mail: mm038492{at}Msat.fukuoka-u.ac.jp

	Abstract

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Abstract. The role of mast cells (MC) in tubulointerstitial damage in glomerulonephritis (GN) is not fully understood. The distribution of MC was compared in renal biopsies from 50 patients with different stages of rapidly progressive GN (RPGN) and in 20 control samples. The immunoreactivity of renal MC with anti-tryptase and anti-chymase antibodies was studied. Interstitial myofibroblasts were stained with anti--smooth muscle actin (-SMA) antibody, and inflammatory cells were identified by anti-CD3, -CD20, and -CD68 monoclonal antibodies. Positively stained cells were counted, and the relative interstitial and fractional areas of anti--SMA-stained cells were measured. MC were rarely found in control samples. In contrast, samples showing crescentic GN contained numerous tryptase-positive MC (MC_T) (43.7 ± 4.65 versus 7.14 ± 1.3/mm²) and fewer tryptase- and chymase-positive MC (MC_TC) (13.8 ± 1.86 versus 1.89 ± 0.86/mm²) in the renal interstitium but never in the glomerulus. Double immunostaining demonstrated the presence of both phenotypes of MC. Accumulation of MC was significantly correlated with the numbers of T lymphocytes (MC_T, r = 0.67) and interstitial macrophages (MC_T, r = 0.455). There was also a significant correlation between the number of MC_T and the relative interstitial area. The number of MC_TC was well correlated with the fractional area of -SMA-positive interstitium (r = 0.749) and the percentage of the interstitial fibrotic area (r = 0.598). There was also a significant negative correlation between interstitial MC_TC accumulation and creatinine clearance (r = 0.661). The density of MC_TC was higher (1.4-fold) in advanced forms of GN associated with fibrocellular crescents and interstitial fibrosis. These results show the potential involvement of MC in the fibroproliferative process in the renal interstitium of patients with RPGN. The results indicate that these cells constitute part of the overall inflammatory cell accumulation in RPGN.

	Introduction

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Tubulointerstitial (TI) lesions are considered prognostic features of various renal diseases. Despite numerous studies in human subjects and experimental animal models, the exact pathogenic factors involved in TI damage remain unclear. In particular, the role of mast cells (MC) in glomerulonephritis (GN) with TI lesions has not yet been fully analyzed. MC play an important role in allergic inflammatory conditions such as asthma, and their number is increased in chronic inflammatory conditions. Their presence in tissue is often accompanied by fibrosis, such as liver cirrhosis, pulmonary fibrosis, and wound healing, suggesting that they might be involved in these pathologic conditions (1,2,3).

Immunohistochemical studies have demonstrated the presence of two MC phenotypes, which are distinguished by their neutral serine protease contents. The tryptase-positive MC (MC_T) phenotype contains only tryptase, whereas the tryptase- and chymase-positive MC (MC_TC) phenotype contains both tryptase and chymase (4). The MC_T phenotype seems to play a role in host defense, whereas the MC_TC phenotype seems to represent "non-immune system-related" cells involved in fibrosis (5). MC have been demonstrated by histochemical or immunohistochemical methods in various renal diseases, including nephrosclerosis, pyelonephritis, chronic GN, amyloidosis (6,7), renal vasculitis (8), acute cellular rejection of renal allografts (9) and IgA nephritis (10). Furthermore, both MC phenotypes have been detected in diabetic nephropathy (11). There is general agreement that MC increase in number during chronicity and progression of various renal lesions (6,9,11)

Activated MC synthesize, store, and release several bioactive mediators. For example, histamine and heparin are mitogenic for fibroblasts and induce collagen synthesis, as well as activating collagenase (12,13,14,15,16,17). MC are also known to secrete basic fibroblast growth factor in IgA nephritis (10). Using the in situ hybridization technique, Ruger et al. (11) demonstrated that human MC can produce type VIII collagen both in vitro and in vivo in diabetic nephropathy. However, whether MC modulate the inflammatory and fibrotic processes in GN remains to be elucidated.

In this study, we evaluated the potential role of MC in the pathogenesis of TI lesions in rapidly progressive GN (RPGN), which is characterized by glomerular crescent formation, marked inflammatory processes, and TI fibrosis. Specifically, we examined the role of MC in the fibrotic process in TI lesions.

	Materials and Methods

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Definition
RPGN was defined as glomerular disease with extensive glomerular crescent formation (>50%) associated with rapid loss of renal function (usually 50% reduction of GFR within 3 mo).

Tissue Samples
Kidney tissue samples were obtained from 50 randomly selected patients (23 men and 27 women; mean age, 53.3 ± 15.7 yr) with crescentic GN at the time of renal biopsy. Only samples containing at least 10 glomeruli in the paraffin blocks were included in this study. All samples showed extensive crescent formation in >50% of the glomeruli. Histologic studies using light, immunofluorescence, and electron microscopy demonstrated typical extracapillary cell proliferation with crescent formation. Patients with RPGN were divided into three subgroups on the basis of the etiologic classification criteria of Couser (18) (Table 1). Control samples consisted of 20 randomly selected renal biopsy samples from patients with thin glomerular membrane disease, with normal extraglomerular renal structure and without immune deposition, glomerulosclerosis, or inflammation. All patients in both groups were adults (>16 yr of age). Clinical and laboratory data were recorded at the time of renal biopsy. The study protocol was approved by the Human Ethics Review Committee of Fukuoka University, and signed consent forms were obtained.

Patients with RPGN were divided into two groups according the type of glomerular crescents. Stage I tissue samples (n = 25) contained fresh large cellular crescents around the glomerular capillary tufts, representing early stages of the disease process. Stage II tissue samples (n = 25) contained fibrocellular crescents in more than one-half of the crescentic glomeruli, representing a progressive glomerular process with or without interstitial fibrosis.

Tissue Preparation
Tissue sections were stained with hematoxylin and eosin, Masson's trichrome, periodic acid-Schiff, and periodic acid-methenamine-silver stains. To identify MC, sections were stained with toluidine blue.

Electron Microscopy
A portion of each biopsy sample was fixed in 1.4% phosphate-buffered glutaraldehyde, post-fixed in OsO₄, and embedded in Epon resin. Ultrathin sections were cut and stained with uranyl acetate and lead citrate. All samples were examined by electron microscopy.

Immunohistochemical Analyses
Anti-human chymase rabbit IgG (protein-origin antibody) was obtained using the methods described previously (19). Peptide-origin monoclonal antibody for chymase was a kind gift from Drs. Y. Kiso and N. Ishihara of Suntory Biomedical Research Center (Osaka, Japan). Anti-human tryptase monoclonal antibody was purchased from Chemicon International (Temecula, CA). Anti-CD68, anti-CD20, anti-CD3, and anti--smooth muscle actin (-SMA) monoclonal antibodies were purchased from Dako (Glostrup, Denmark). For immunohistochemical staining of the tissue samples, one part of each biopsy sample was fixed for light microscopy in 10% buffered formalin and was embedded in paraffin. Three-micrometer-thick, deparaffinized, serial sections were washed in 0.05 M Tris-HCl buffer containing 0.145 M NaCl, pH 7.5 (Tris-buffered saline [TBS]). Protease pretreatment was performed for staining for chymase and CD68, whereas autoclave pretreatment (121°C, 10 min) was performed for staining for -SMA. Sections were initially treated with 1% skim milk (DIFCO Laboratories, Detroit, MI) and incubated for 1 h at 20°C with the first antibody (anti-chymase antibody, 50 mg/ml; anti-tryptase antibody, 0.32 mg/ml; each dissolved in 3% bovine serum albumin). For negative control staining, we used vehicle alone or nonimmunized animal Ig. After incubation, sections were washed with TBS and then incubated for 30 min with alkaline phosphatase (ALP)-conjugated second antibody against rabbit or mouse Ig (Dako). After washing, sections were incubated for 30 min with ALP-conjugated third antibody against ALP (Dako). The sections were then stained with a solution of 0.01% new fuchsin (Merck, Darmstadt, Germany), 0.01% NaN, 10 mg of naphthol AS-BI phosphate (Sigma Chemical Co., St. Louis, MO), and 0.1 ml of N,N-dimethylformamide (Wako, Osaka, Japan) in 40 ml of 0.2 M Tris-HCl buffer, pH 8.2. After being washed with TBS, sections were post-fixed in 2% buffered glutaraldehyde, counterstained with hematoxylin, and used for immunohistochemical detection.

In a preliminary study, we immunohistochemically compared two different antibodies for human chymase, i.e., a peptide-origin antibody and a protein-origin antibody (Chemicon International). The results showed that the two antibodies yielded similar precisions; therefore, the protein-origin antibody was used in the following experiments. Tissue for positive controls consisted of biopsy samples from the small intestine for chymase and tryptase and the renal vasculature for -SMA.

Double Immunostaining
After deparaffinized sections were treated with 0.005% protease (Dako-Japan, Osaka, Japan) for 10 min, they were incubated for 60 min at 20°C with the first mouse antibody against human chymase (Chemicon). After being washed with TBS, sections were incubated for 60 min at 20°C with tetrarhodamine isothiocyanate-conjugated second rabbit antibody against mouse Ig (Dako). Sections were then treated with 1% skim milk for 30 min to minimize the background levels. Sections were again incubated with the first rabbit antibody against human tryptase (BioPur Co., Switzerland), for 60 min at 20°C. After being washed with TBS, sections were incubated for 60 min at 20°C with FITC-conjugated swine antibody against rabbit Ig (Dako). In the next step, nuclei were stained with 4',6-diamidino-2-phenylindole (Sigma). Sections were then mounted and examined under a fluorescence microscope (Axioplan; Carl Zeiss, Jena, Germany), with a fluorescence imaging system (Isis; MetaSystems, Altlussheim, Germany).

Morphometric Analyses
Several indices of the extent of the pathologic processes were derived using a previously published method (20). (1) A standard point-counting method was used to quantify the relative interstitial area (A_int) of the renal cortex. In this method, sections stained by the periodic acid-methenamine-silver method were examined under high magnification (x400), using a 121-point (100-square) eyepiece micrometer of 1 mm². A total of 10 consecutive nonoverlapping cortical fields (area, 0.625 mm²) were analyzed in each section of the biopsy. Points overlying the tubular basement membrane and interstitial space were counted, whereas those falling on either Bowman's capsule or the peritubular capillaries were not. Points falling on glomerular structures or on larger vessels were excluded from the total count. The results were expressed according to the following formula: A_int = [(Number of grid intersections on the cortical interstitium/Total number of grid intersections) x 100]. (2) Interstitial immunoperoxidase staining for -SMA was quantified by the point-counting method described above. The fractional area was also calculated, using the formula given above. (3) The fractional area stained by Masson's trichrome stain was quantified by the point-counting method described above, and the results were expressed as the fractional area using the formula given above. (4) The numbers of interstitial lymphocytes (CD20⁺ and CD3⁺) and macrophages (CD68⁺ and Ki-1⁺) present in the cortical interstitial area were counted, under high magnification (x400), in 10 adjacent nonoverlapping cortical fields (total area, 0.625 mm²/biopsy specimen). Only cells with a clearly identifiable nucleus were counted. Finally, the number of counted cells was expressed as cells per unit area (square millimeter).

Statistical Analyses
Data were expressed as mean ± SEM. Differences between groups were examined for statistical significance using the t test and one-way ANOVA. Association of categorical variables was examined using the ² test. Correlation between variables was assessed by linear regression analysis. A P value of <5% denoted a statistically significant difference.

	Results

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Immunohistochemical Observations
A representative tissue sample containing MC_T is shown in Figure 1. Double staining for both proteases showed MC positive for tryptase only, whereas others were stained for both tryptase and chymase (Figure 2). Chymase was not observed in cells lacking tryptase. MC were mostly round in shape, with a central nucleus and abundant cytoplasm containing numerous tryptase- or chymase-positive granules (Figure 3, inset). A proportion of MC appeared elongated, with cytoplasmic processes, and contained fewer granules. Electron-microscopic examination clearly demonstrated the presence of numerous intracytoplasmic dense granules (Figure 3). MC were localized in the peritubular or periglomerular region, in close proximity to interstitial fibroblasts (Figure 3), and were surrounded by cell processes of fibroblasts. Intraglomerular MC were never detected in our tissue samples, although a few intratubular MC_T and/or MC_TC were found. MC were mostly located on the periphery, rather than within areas of lymphocytic accumulation. Furthermore, MC were observed around interstitial CD68⁺ macrophages and -SMA-positive interstitial areas (Figure 4).

View larger version (150K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Photomicrograph showing diffusely distributed tryptase-positive mast cells (MCT) in the renal interstitium. Magnification, x200.

View larger version (48K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Photomicrograph showing both phenotypes of mast cells (MC). The MCT phenotype is indicated by rhodamine-labeled tryptase particles (red). The tryptase- and chymase-positive (MCTC) phenotype is shown as yellow, mixing the rhodamine-labeled tryptase (red) and FITC-labeled chymase (green). Note the absence of only chymase-positive MC. Double immunostaining; magnification, x200.

View larger version (145K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Photomicrograph showing peritubular (T) MC. An oval-shaped MC completely filled by electron-dense granules is in the interstitium (INT). The MC is partially surrounded by cytoplasmic processes (arrows) of a peritubular interstitial fibroblast (F). Electron microscopy; magnification, x6000. Inset, granulated MCT. Immunostaining; magnification, x1000.

View larger version (128K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Two serial 3-µm sections of a rapidly progressive glomerulonephritis (RPGN) renal biopsy, immunostained for chymase (a) and -smooth muscle actin (-SMA) (b). Note that MCTC accumulation is colocalized with the -SMA-positive myofibroblast proliferation area. Magnification, x400.

The densities of both MC phenotypes were significantly higher in the RPGN group than in control samples (MC_T, 43.7 ± 4.6 versus 7.1 ± 1.3/mm²; MC_TC, 13.8 ± 1.86 versus 1.9 ± 0.86/mm²). Specifically, the MC_T phenotype was the predominant MC type, whereas fewer MC_TC were found in the study group. Furthermore, MC constituted the third most abundant interstitial inflammatory cell population in RPGN (Figure 5). Figure 5 shows the distribution of both MC types in relation to the development of RPGN. The numbers of MC in different types of RPGN were not significantly different and were less than the numbers of T cells.

View larger version (31K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Distribution of renal interstitial inflammatory cells in cases of RPGN, according to etiologic differences. Mo/Ma, monocytes/macrophages.

We also analyzed the distribution of different MC subsets according to the histologic stages of RPGN. No major difference was observed in the number of MC_T (41.8 ± 6.5 versus 45.8 ± 6.7/mm²). However, the mean number of MC_TC was higher (1.4-fold) in stage II than in stage I (11.4 ± 1.9 versus 16.2 ± 3.1/mm², P > 0.05), although the difference was not statistically significant. In stage II, representing a progressive form of RPGN, inflammatory cells (T cells, B cells, and macrophages) were more abundant than in stage I, but the difference was not significant.

Morphometric Correlation
We also analyzed the correlation between the MC phenotype and the pathologic findings. There was a significant correlation between the percentage of glomerular crescents and the number of MC_T (r = 0.497, P < 0.001). Furthermore, there was a significant correlation between the number of interstitial T lymphocytes and the number of MC_T (r = 0.67, P < 0.0001), as well as that of MC_TC (r = 0.719, P < 0.0001). However, there was no relationship between the density of B cells and the numbers of MC_T and MC_TC (r = 0.358 and 0.238, respectively; P > 0.05). There was a significant correlation between the number of interstitial CD68⁺ macrophages and the numbers of MC_T (r = 0.455, P < 0.001) and MC_TC (r = 0.646, P < 0.0001). A significant relationship was detected between the relative interstitial volume (reflecting all changes associated with interstitial expansion, such as edematous expansion, focal fibrosis, and inflammatory cell accumulation) and the number of MC_T (r = 0.45, P < 0.0014).

A close relationship was observed between the fractional area of -SMA staining and the number of MC_TC (r = 0.749, P < 0.0001) (Figure 6), but this relationship was weaker with MC_T (r < 0.525, P < 0.0001). The fractional area of fibrosis was significantly higher in stage II RPGN than in the early stage (stage I) of the disease (10.8 ± 9.4 versus 23.7 ± 14.9%, P = 0.0006). In addition, there was a significant correlation between the fractional area of fibrosis and the number of MC_TC but not that of MC_T (r = 0.598, P < 0.0001, compared with r = 0.269, P > 0.05).

View larger version (21K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 6. Correlation between the number of MCTC and the fractional area of -SMA-positive cell proliferation (FA-SMA).

Clinicopathologic Correlation
The number of MC was not influenced by age or gender but was significantly correlated with serum creatinine clearance, particularly for MC_TC (r = 0.661, P < 0.0001). Furthermore, significantly greater numbers of MC_TC were detected in patients with hypertension (> 165/95 mmHg, n = 16), including MC_TC (22.4 ± 15.3 versus 9.7 ± 9.8/mm², P < 0.0001).

	Discussion

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The major finding of this study was the significant accumulation of both MC phenotypes in RPGN (sixfold), compared with control cases. Although MC have been demonstrated previously in renal diseases (6,7,8,9,10,11), to our knowledge this is the first demonstration, using the double immunostaining method, of the simultaneous presence of both MC_T and MC_TC phenotypes in RPGN. Accumulation of MC in the interstitium was significantly correlated with the loss of renal function, as reported for other renal diseases (9,10), and was well correlated with TI damage.

In the early stages, RPGN is histologically characterized by extracapillary glomerular epithelial cell proliferation associated with intra- and extraglomerular inflammation. However, with the progression of the disease process, histologic examination usually shows fibrocellular and then fibrous transformation of the glomerular crescents, together with TI damage, including interstitial fibrosis. Our data suggest the presence of MC in both stages of renal lesions, but the MC_TC phenotype is more frequently (1.4-fold) present in the late stage than in the early stage. Despite the report in 1960 of the detection of MC in "subacute GN" (7), the mechanism by which MC proliferate in the interstitium in RPGN is still not known.

Consistent with the results of recent studies (6,7,8,9,10,11), our findings showed that MC were localized in the renal interstitium but not in the glomerular tufts or spaces. Although our results showed a good correlation between the number of MC and the frequency of glomerular crescents, the distribution of these cells indicated that MC accumulation was correlated more strongly with TI injury than with glomerular lesions.

More importantly, we also demonstrated a strong correlation between the number of MC_TC and TI damage of RPGN, including inflammation, myofibroblast proliferation, and fibrosis.

The results depicted in Figure 5 showed no differences in the accumulation of MC and that of other types of inflammatory cells in different types of RPGN. These results suggest that infiltration of MC is an integral part of the inflammatory process, rather than a specific process in these renal diseases. In this regard, previous studies have convincingly demonstrated that the pathologic processes in these nephropathies are dependent to a large extent on inflammatory cells, especially T cells and macrophages (21,22). Although no correlation was observed between the accumulation of MC and that of B lymphocytes in previous studies (9,10,11), histologic examination and morphometric analysis in this study revealed a close relationship between the accumulation of MC and that of T lymphocytes. Previous in vivo and in vitro studies established that MC maturation and activation is regulated by products of T lymphocytes (e.g., interleukin-3 and interleukin-4) (23,24). Therefore, it is possible that infiltration of T cells in the interstitium in RPGN might directly or indirectly increase MC ingress from the circulation, as well as MC maturation and activation. Furthermore, it has been demonstrated that tryptase can also increase microvascular permeability (25), enhance inflammatory cell transmigration (26), and stimulate maturation as well as cytokine release (5,27). Additional studies are necessary to determine whether MC or lymphocytes can initiate the induction of interstitial inflammation and whether activated T cells within the diseased kidney synthesize molecules that participate in MC proliferation and maturation or vice versa. Although our analysis demonstrated a close structural and statistical relationship between monocyte/macrophages and MC, similar to previous data on human lung MC activation by macrophage inflammatory protein-1 (28), the functional relationship between these cells in renal diseases is still not clear.

In this study, we found colocalization of accumulated MC and -SMA-positive myofibroblasts, indicating that MC may be involved in the fibrotic process in RPGN. Previous studies described the presence of MC in fibrotic areas of various organs (1,2,3,29,30). For example, Li et al. (30) found that cardiofibrosis was more severe when a large proportion of MC were present in heart transplants. Furthermore, Lajoie et al. (9) demonstrated a strong relationship between the number of MC_T and interstitial edema, as well as fibrosis, in renal allografts. However, in another study, despite the significant (10-fold) accumulation of MC, Colvin et al. (6) did not detect any correlation between interstitial damage and the accumulation of MC in chronic rejection in renal allografts stained with toluidine blue. The discrepancy between these results might be attributable to different methods used for the identification of MC. Despite the in vitro effects of MC on the development of fibrosis (31,32), the role of MC in fibrogenesis in GN has not been demonstrated. In this analysis, there was a significant correlation between the accumulation of both phenotypes of MC (particularly the MC_TC phenotype) and the degree of interstitial fibrosis. The density of MC_TC in the late stage of RPGN was higher than that in the early stage. Whether selective proliferation or activation of a MC_TC subpopulation occurs in RPGN remains to be elucidated.

Consistent with previous observations (10), we also found a close structural relationship between MC and interstitial fibroblasts (Figure 3, inset). The latter cells are known to take up MC granules (33), followed by phenotypic modulation of MC by cytokines (34). Furthermore, MC products (e.g., tryptase, chymase, and histamine) have mitogenic activity for fibroblasts and enhance collagen synthesis (12,13,14,16,17,32,35). Recently, mitogenic basic fibroblast growth factor was detected in renal MC cytoplasm in biopsy specimens from patients with IgA nephritis (10), suggesting the potential fibrogenic role of MC in IgA nephritis. On the other hand, in vitro and in vivo analyses demonstrated that MC products such as heparin and tumor necrosis factor- influence -SMA expression (32,35). Ruger et al. (11) observed periglomerular accumulation of MC, type VIII collagens, and -SMA-positive cells in diabetic nephropathy, suggesting that MC may upregulate renal fibroblasts expressing -SMA. These activated fibroblasts (myofibroblasts) are well known as the cells responsible for extracellular matrix production (36,37) in renal fibrosis. Our results demonstrated a significant correlation between the accumulation of both phenotypes of MC and the fractional area of -SMA staining, suggesting that the role of MC is not only in the early inflammatory process but also in the late fibrotic renal process in RPGN.

In summary, this study demonstrated that MC accumulation is a feature of a more aggressive form of RPGN and that such accumulation may be an important mechanism for amplifying MC-mediated renal injury. Additional studies are necessary to clarify the exact role of MC in renal inflammatory and fibroproliferative processes. Understanding the mechanisms for MC interstitial inflammation and fibrosis may facilitate the design of new therapeutic strategies for the treatment and prevention of GN progression.

	Acknowledgments

 
Acknowledgments

We are grateful to Drs. Y. Kiso and N. Ishihara of the Suntory Biomedical Research Center (Osaka, Japan) for providing anti-chymase antibody. We also thank Noriko Kawamoto and Masako Ishiguro for skilled technical assistance and Dr. F. G. Issa (Word-Medex, Sydney, Australia) for careful reading and editing of the manuscript.

	Footnotes

 
American Society of Nephrology

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Claman HN: Mast cells, T cells and abnormal fibrosis. Immunol Today 6:192 -195, 1985
2. Metcalfe DD, Costa JJ, Burd PR: Mast cells and basophils. In: Inflammation: Basic Principles and Clinical Correlates, 2nd Ed., edited by Gallin JI, Goldstein IM, Snyderman R, New York, Raven Press, 1992, pp709 -725
3. Ambrust T, Batusic D, Ringe B, Ramadori G: Mast cell distribution in human liver disease and experimental rat liver fibrosis: Indications for mast cell participation in development of liver fibrosis. J Hepatol 26:1042 -1054, 1997[Medline]
4. Irani AM, Schechter NM, Craig SS, DeBlois G, Schwartz LB: Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 83:4464 -4468, 1986[Abstract/Free Full Text]
5. Church MK, Levi-Schaffer F: The human mast cell: Updates on cells and cytokines. J Allergy Clin Immunol99 : 155-160,1997[Medline]
6. Colvin RB, Dvorak AM, Dvorak HF: Mast cells in the cortical tubular epithelium and interstitium in human renal disease. Hum Pathol 5:315 -326, 1974[Medline]
7. Pavone-Macalusco M: Tissue mast cells in renal diseases. Acta Pathol 50:337 -346, 1960
8. Harrison DJ, Neary C, Wathen CG: Distribution of IgE-bearing cells in renal biopsies in Wegener's granuloma. Nephrol Dial Transplant 3:24 -27, 1988[Abstract/Free Full Text]
9. Lajoie G, Nadasdy T, Laszik Z, Blick K, Silva FG: Mast cells in acute cellular rejection of human renal allografts. Mod Pathol 9:1118 -1125, 1996[Medline]
10. Ehara T, Shigematsu H: Contribution of mast cells to the tubulointerstitial lesions in IgA nephritis. Kidney Int 54:1675 -1683, 1998[Medline]
11. Ruger BM, Hasan Q, Greenhill NS, Savis PF, Dunbar PR, Neale TJ: Mast cells and type VIII collagen in human diabetic nephropathy. Diabetologia 39:1215 -1222, 1996[Medline]
12. Russel JD, Russel SB, Trupin KM: The effect of histamine on the growth of cultured fibroblasts isolated from normal and keloid tissue. J Cell Physiol 93:389 -394, 1977[Medline]
13. Norrby K: Effect of heparin, histamine and serotonin on the density-dependent inhibition of replication in two fibroblastic cell lines. Virchows Arch B Cell Pathol 15:75 -93, 1973
14. Hatamochi A, Fujiwara K, Ueki H: Effects of histamine on collagen synthesis by cultured fibroblasts derived from guinea pig skin. Arch Dermatol Res 277:60 -64, 1985[Medline]
15. Folkman J, Kagsbrun M: Angiogenic factors. Science 235:442 -447, 1987[Abstract/Free Full Text]
16. Young JD-E, Liu CC, Butler G, Cohn ZA, Galli SJ: Identification, purification, and characterization of a mast cell-associated cytolytic factor related to tumor necrosis factor. Proc Natl Acad Sci USA 84:9175 -9179, 1987[Abstract/Free Full Text]
17. Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM: Recombinant human tumor necrosis factor-: Effects on proliferation of normal and transformed cells in vitro. Science 230:943 -945, 1985[Abstract/Free Full Text]
18. Couser WG: Rapidly progressive glomerulonephritis: Classification, pathogenetic mechanisms, and therapy. Am J Kidney Dis11 : 449-464,1988[Medline]
19. Urata H, Kinoshita A, Misono KS, Bumpus FM, Hussain A: Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem265 : 22348-22357,1990[Abstract/Free Full Text]
20. Tóth T, Takebayashi S: Glomerular hypertrophy as a prognostic marker in childhood IgA nephropathy. Nephron 80:285 -291, 1998[Medline]
21. Hooke DH, Gee DC, Atkins RC: Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int31 : 964-972,1987[Medline]
22. Lan HY, Nikolic-Paterson DJ, Mu W, Atkinson RC: Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int48 : 753-760,1995[Medline]
23. Nabel G, Galli SJ, Dvorak AM, Dvorak HF, Cantor H: Inducer T lymphocytes synthesize a factor that stimulates proliferation of cloned mast cells. Nature (Lond) 291:332 -334, 1981[Medline]
24. Bhattacharyya SP, Drucker I, Reshef T, Kirshenbaum AS, Metcalfe DD, Mekori YA: Activated T lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact. J Leukocyte Biol 63:337 -341, 1998[Abstract]
25. He S, Walls AF: Mast cell tryptase: A stimulus of microvascular leakage and mast cell activation. Eur J Pharmacol328 : 89-97,1997[Medline]
26. He S, Peng Q, Walls AF: Potent induction of neutrophil and eosinophil-rich infiltrate in vivo by human mast cell tryptase: Selective enhancement of eosinophil recruitment by histamine. J Immunol 159:6215 -6225, 1997
27. Cairns JA, Walls AF: Mast cell tryptase is a mitogen for epithelial cells: Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol 56:275 -283, 1996
28. Baghestanian M, Hofbauer R, Kiener HP, Bankl HC, Wimazal F, Willheim M, Scheiner O, Fureder W, Muller MR, Bevec D, Lechner K, Valent P: The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells. Blood 90:4438 -4449, 1997[Abstract/Free Full Text]
29. Inoue Y, King TE Jr, Tinkle SS, Dockstader K, Newman LS: Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol 149:2037 -2054, 1996[Abstract]
30. Li Q-Y, Raza-Ahmad A, MacAulay MA, Lalonde LD, Rowden G, Trethewey E, Dean SH: The relationship of mast cells and their secreted products to the volume of fibrosis in posttransplant hearts. Transplantation 53:1047 -1051, 1992[Medline]
31. Rubinchik E, Levi-Schaffer F: Mast cells and fibroblasts: Two interacting cells. Int J Clin Lab Res24 : 139-142,1994[Medline]
32. Cairns JA, Walls AF: Mast cell stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest99 : 1313-1321,1997[Medline]
33. Subba Rao PV, Friedman MM, Atkins FM, Metcalfe DD: Phagocytosis of mast cell granules by cultured fibroblasts. J Immunol130 : 341-349,1983[Abstract]
34. Davidson S, Mansour A, Gallily R, Smolarski M, Rofolovitch M, Ginsburg H: Mast cell differentiation depends on T cells and granule synthesis on fibroblasts. Immunology 48:439 -452, 1983[Medline]
35. Desmouliere A, Rubbia-Brandt L, Grau G, Baggiani G: Heparin induces -smooth muscle actin expression in cultured fibroblasts and in granulation tissue myofibroblasts. Lab Invest67 : 716-726,1992[Medline]
36. Alpers CE, Hudkins KL, Floege J, Hohnson RJ: Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury. J Am Soc Nephrol 5:201 -210, 1994[Abstract]
37. Goumenos D, Tsomi K, Iatrou C, Oldroyd S, Sungur A, Papaioannides D, Moustakas G, Ziroyannis P, Mountokalakis T, El Nahas AM: Myofibroblasts and the progression of crescentic glomerulonephritis. Nephrol Dial Transplant 13:1652 -1661, 1998[Abstract/Free Full Text]

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