Presence of c-KIT-positive mast cells in obliterative bronchiolitis from diverse causes.
Our interest in the pathogenesis of obliterative bronchiolitis was spurred by a case of a 59-year-old woman who developed progressive shortness of breath after exposure to household cleaning supplies while cleaning a relative's attic. Her symptoms progressed during an 18-month period, ultimately resulting in a lung transplant. Of particular interest was the inflammatory response, which included many mast cells associated with fibrosis of small airways in this case of obliterative bronchiolitis.
In addition to the previously mentioned case, an explanted lung specimen demonstrating obliterative bronchiolitis after massive ammonia exposure prompted us to examine the role of mast cells in chemical inhalation and to compare it to obliterative bronchiolitis due to other causes. We also wanted to study the differences between obliterative bronchiolitis and nonfibrosing conditions, such as asthma and chronic obstructive pulmonary disease, as controls for c-KIT (CD117)-positive mast cells. Of interest was the pathogenesis of the persistent and progressive fibrosis noted in these cases, long after acute inhalation exposure and despite the lack of long-term inhalation exposure, along with the differences between involved and uninvolved airways. In addition, we examined stem cell factor (SCF), a ligand of c-KIT (CD117), in lung fibrosis conditions, as its role is still unclear.
MATERIALS AND METHODS
Case records from the previous 20 years were reviewed for all diagnoses of obliterative bronchiolitis in our 2 hospitals. Four cases with blocks available for study were selected. We examined 2 cases of obliterative bronchiolitis secondary to massive chemical exposures (1 due to unknown household cleaners and 1 due to massive ammonia exposure). Both of the cases were remarkable for new and old scarring lesions at the time of explant pneumonectomy. Also selected were 2 cases of nonexposure obliterative bronchiolitis, including one transplant pneumonectomy for idiopathic obliterative bronchiolitis and a second case of post-transplantation obliterative bronchiolitis diagnosed in a post-transplantation wedge biopsy specimen. In addition, we compared these 4 cases of obliterative bronchiolitis to a control group, which included 2 explant pneumonectomies for emphysema with the additional clinical diagnosis of asthma, and 2 explant pneumonectomies for emphysema alone. Representative blocks of formalin-fixed, paraffin-embedded tissue were selected from each case with blocks containing both small and large airways. Two to 3 representative blocks were selected from each case to allow sufficient tissue for examination of at least 10 small airways (ie, bronchioles that do not bear alveoli or cartilage) and 5 larger airways (ie, with associated cartilage). All airways in each chosen block were examined. The only exception was the case of post-transplantation obliterative bronchiolitis diagnosed in a wedge biopsy, which consisted of 2 blocks containing only small airways with no larger airways available for examination.
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The hematoxylin-eosin-stained sections for each case were initially examined to confirm all original diagnoses. The representative blocks chosen from each case were then stained with immunohistochemical stains including CD20, CD3, CD4, CD8, CD34, CD25, and CD117 (c-KIT) along with special stains including toluidine blue and Giemsa stain. All selected blocks were stained with Gomori trichrome to examine the amount of fibrosis in individual airways.
After the examination of all immunohistochemical and special stains, the c-KIT (CD117)-stained slides were digitally scanned using Aperio ScanScope software (Vista, California). The c-KIT (CD117)-positive cells were manually counted from the digital images of the slides. The c-KIT (CD117)-positive cells within the epithelium of airways were counted and recorded. This step was followed by the counting and recording of the number of c-KIT (CD117)-positive cells within the subepithelium. The subepithelium was designated as the connective tissue immediately surrounding each individual airway, including muscular layer and adventitial connective tissue. The number of positive cells was standardized per millimeter of airway basement membrane. The basement membrane measurement was made using Aperio ScanScope software measuring tools. CD34 stains on all blocks were reviewed and then subjectively compared to c-KIT (CD117) stains to further verify that the c-KIT (CD117)-positive mature mast cells were negative for CD34 staining. Comparison was accomplished with Aperio ScanScope software split-screen application. Immunohistochemical staining on all previously selected blocks was also done for stem cell factor (SCF; c-KIT ligand) and CD25 and compared to c-KIT (CD117) staining.
The 4 cases of obliterative bronchiolitis as a group showed a dramatic increase in staining for c-KIT (CD117)-positive mast cells within the subepithelium of small airways (122.0 cells/mm of basement membrane) (Figure 1, A through D; Table 1, A through D) when compared to asthma and emphysema controls (25.3 cells/mm) (Figure 2, A through D; Table 1, E through H). The asthma and emphysema controls, however, showed relatively more mast cells within the airway epithelium (7.2 cells/mm) (Figure 2, A through D; Table 1, E through H) when compared to the obliterative bronchiolitis cases (1.9 cells/mm) (Figure 1, A through D; Table 1, A through D).
The ratio of mast cells in the subepithelium to mast cells in the epithelium of small airways was markedly increased in cases of obliterative bronchiolitis when compared to this same ratio in cases of asthma and emphysema (65.9:1 versus 3.8:1) (Table 2). The overall number of c-KIT (CD117)-positive cells within the subepithelium of large airways was not notably greater in obliterative bronchiolitis cases (57.9 cells/mm) (Figure 1, A through D; Table 1, A through D) when compared to control cases (41.4 cells/mm) (Figure 2, A through D; Table 1, E through H). However, large airways did show relative increased mast cell concentrations within the subepithelium in the obliterative bronchiolitis cases (37.0 cells/mm) when compared to controls (3.1 cells/mm) (Table 2).
A distinction in the overall amount of c-KIT (CD117) staining between the cases of chemical exposure and the other cases of obliterative bronchiolitis was not made, but the staining of c-KIT (CD117) did appear to reflect the severity of fibrosis within individual small airways. c-KIT (CD117) staining appeared to have a relationship to the individual airway involvement in the case of obliterative bronchiolitis from ammonia exposure (case B), as was made evident by the difference between staining in the subepithelium of 9 airways with fibrosis (51.5 cells/ mm) (Figure 3, A; Table 3) and 2 airways uninvolved by fibrosis (13.8 cells/mm) (Figure 3, B; Table 3). The amount of fibrosis also seemed to correlate with staining from a case to case standpoint, as our initial case of obliterative bronchiolitis due to household cleaner inhalation (case A) (Figure 1, A; Table 1, A) had the most severe fibrosis of all cases examined, with a corresponding marked increase in the amount of c-KIT (CD117) staining.
Subjective comparison of B- and T-cell populations by immunohistochemistry was performed and no distinction was detected between the obliterative bronchiolitis and control cases. Toluidine blue staining performed on all blocks was examined for metachromatic granules and correlated to the c-KIT (CD117) staining as verification of mast cells. c-KIT (CD117)-positive cells around airways were negative for CD34, confirming the presence of mature mast cells. Giemsa staining was performed on all blocks, but was noncontributory because of nonspecific staining. Stem cell factor (c-KIT ligand) failed to show staining within the epithelium or subepithelium of small and large airways in all cases despite strong internal control staining of interstitial macrophages. CD25 demonstrated scattered nonspecific staining but was negative in mast cells concentrated around airways.
The mature mast cell has been implicated as an important player in fibrogenesis. The mast cell's ability to synthesize and release cytokines such as interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13) and other chemotactic factors has given acceptability to its role in the asthmatic inflammatory response, and the chemical pathway to inducing fibrosis is of particular interest. (13-15) The relationship of mast cells and fibroblasts to movement, activity, and proliferation has been demonstrated along with the production of multiple mediators of fibrogenesis including vascular endothelial growth factor, fibroblast growth factor 2, platelet-derived growth factor, and transforming growth factor [beta]. (16,17)
Mast cells have been associated with fibrosing diseases throughout the body, such as primary sclerosing cholangitis in the liver. Tsuneyama et al (18) reported an association between increased mast cells surrounding fibrosed bile ducts and aberrant SCF expression in the epithelium of the bile ducts.
In the lung, fibrosing diseases like idiopathic pulmonary fibrosis/usual interstitial pneumonitis, lymphangio-leiomyomatosis, and idiopathic obliterative bronchiolitis have increased numbers of mast cells. (16,19-22) Other nonfibrotic pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, have also been associated with increased numbers of mast cells. (13,23-25) Pesci et al indicated involvement of mast cells in chronic inflammation leading to fibrosis in a variety of fibrotic lung diseases. They based their conclusions on an increased number of mast cells, especially located within connective tissue rich in fibroblasts, which correlated with the degree of fibrosis. They noted these findings in cryptogenic fibrosing alveolitis, sarcoidosis, farmer's lung disease, histiocytosis, and also bronchiolitis obliterans organizing pneumonia (BOOP). (21) Earlier studies have demonstrated similar results with the first 3 disease entities. A few years later, Pesci et al (16) furthered previous work by studying the cell composition of bronchoalveolar lavage fluid and the mast cell concentration in transbronchial biopsies of patients with BOOP. They demonstrated increased mast cells both in bronchoalveolar lavage fluid and within septal and intra-alveolar compartments in biopsy specimens, but could not demonstrate a correlation between bronchoalveolar lavage and biopsy results. (16) While this suggests that a relationship exists between mast cells and the potentially reversible fibrosis noted in BOOP, their role in the chronic nonreversible fibrosis noted in obliterative bronchiolitis due to chemical exposure and other etiologies is less clear.
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As the use of immunohistochemical analysis has expanded to become a vital diagnostic tool, so has our ability to assess the phenotype of both neoplastic and non-neoplastic disease processes. Regarding mast cells, c-KIT (CD117) is a consistent biologic marker for identification. (26-28) c-KIT (CD117) is expressed by a variety of tissues throughout the body including not only mast cells but also hematopoietic precursors, melanocytes, interstitial cells of Cajal, germ cells, and many sarcomas and carcinomas. (26,29-32) CD34-positive hematopoietic precursors that express the c-KIT receptor are stimulated by SCF to become mature mast cells with a CD34-negative/c-KIT (CD117)-positive phenotype. (14,15,33) Stem cell factor is produced by fibroblasts, epithelial cells, and even by mast cells themselves and appears to be important in the development, activation, and upregulation of mature mast cells and to the induction of mast cell degranulation. (13-15,18,34-36)
In relatively recent years, the use of imatinib (Gleevec, Novartis, East Hanover, New Jersey), a tyrosine kinase inhibitor, has gained acceptance as a therapeutic agent in treating diseases with mutations of the c-KIT receptor (CD117). These mutations result in a proto-oncogene with intrinsic tyrosine kinase activity, well described in gastrointestinal stromal tumors and systemic mastocytosis. (37-41) However, imatinib inhibits wild-type c-KIT and suppress proliferation in targeted cell lines. (27,36-39) While examples of c-KIT mutations resulting in malignant proliferations and the association of kinases and airway inflammation are becoming better understood, the role of the c-KIT signaling pathway in nonmalignant inflammatory lung disease processes associated with mast cell proliferation is still a novel concept. (42)
Therefore, it is of interest that some fibrosing lung diseases may show an increased number of c-KIT-positive mast cells; this may imply a role in the pathogenesis of the disease. In theory, some fibrosing lung diseases could also benefit from imatinib therapy. This notion is strengthened by a recent study by Aono et al (43) in which the drug was found to be effective in preventing progression to fibrosis in a mouse model with bleomycin-induced pulmonary fibrosis. Their conclusions suggest that inhibition of platelet-derived growth factor receptor (PDGFR) by imatinib could prevent the progression of fibrosis by inhibiting lung fibroblasts. Platelet-derived growth factor receptor is produced by mast cells and its receptor is intimately related to the c-KIT receptor (particularly PDGFR-[alpha]). (16,17,37-39)
While our findings are based on a limited sample of cases, our data suggest that c-KIT (CD117)-positive mast cells are concentrated within the subepithelium of small airways in obliterative bronchiolitis, regardless of etiology. The obliterative bronchiolitis cases demonstrate a nearly 5-fold increase of mast cells within the small-airway subepithelium when compared to asthma and emphysema controls. While mast cells are present in the nonfibrosing lung disease controls (asthma and emphysema) in much lower numbers, their numbers appear to be proportionately greater (3- to 4-fold increase) within the epithelium of small airways than within the subepithelium. This suggests that not only is there an increased number of mast cells in fibrosing lung diseases but also that their location in the subepithelium, where fibrosis is taking place, is unique to the disease. To our knowledge, this is a novel finding, not previously reported in other studies linking fibrotic lung diseases and mast cells. The differences seen in subepithelial to epithelial mast cell ratios strengthen this association (66:1 for obliterative bronchiolitis as a group versus 4:1 for asthmatic/emphysema controls, where overt fibrosis is not present except for the remodeling of the basement membrane zone). While an increase in subepithelial mast cells may simply be a result of fibrosis, our findings suggest that they could potentially play a critical role in eliciting the fibrotic response, possibly through PDGFR-[alpha] or via other yet undetermined cytokines. Additionally, the question of which cytokines are responsible for attracting mast cells to this subepithelial area is yet to be answered.
Just as mast cells are found to be concentrated within the subepithelium in small airways, where fibrosis exists, the notable lack of difference in mast cell concentration in the larger airways, which are characteristically devoid of fibrosis in obliterative bronchiolitis, is of note. This is possibly additional evidence that mast cells are intimately associated with fibrosis, which is distinct to small airways. While large airways of obliterative bronchiolitis cases show a modest relative subepithelial concentration of mast cells, overall numbers as a group were not increased when compared to controls. The nearly 4-fold increase in mast cell concentration around fibrosed airways when compared to uninvolved airways in the ammonia exposure case is of particular interest. This observation, coupled with both the histologic correlation confirming more intense fibrosis in our initial household cleaner inhalation case and the obvious increase in c-KIT (CD117) staining when compared to our obliterative bronchiolitis cases, further strengthens the relationship between mast cells and small-airway fibrosis.
Particularly of note was the fact that our data demonstrated no identifiable trends between the chemical exposure cases and other cases of obliterative bronchiolitis. This suggests a common pathway to fibrosis, regardless of the underlying inciting cause, and also suggests that an association between fibrosis and mast cells may broadly exist for the aforementioned diseases of the lung and even of other organs, as previously reported in the literature. The lack of evidence for a correlation with SCF, as previously noted in other studies, suggests the potential for a yet undetermined chemical pathway unique to fibrosing lung disease. Future research in this area may lead to a better understanding of the cellular response and mechanisms that ultimately result in subepithelial fibrosis in small airways. This suggests that therapy aimed at diminishing mast cell concentration and activity in obliterative bronchiolitis could be of benefit for affected patients. Early administration of drugs such as imatinib or PDGF blockers, presently being used to treat neoplastic cell populations with mutations in the c-KIT receptor, could be used in fibrosing lung diseases with increased proliferation of mast cells with the wild-type c-kit receptor gene.
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Neil E. Fuehrer, MD; Alberto M. Marchevsky, MD; Jaishree Jagirdar, MD
Accepted for publication November 04, 2008.
From the Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, Texas (Drs Fuehrer and Jagirdar); and the Department of Anatomic Pathology, Cedars-Sinai Medical Center, Los Angeles, California (Dr Marchevsky).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Jaishree Jagirdar, MD, Department of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229 (e-mail: Jagirdar@uthscsa.edu).
Table 1. Count of c-KIT (CD117)-Positive Mast Cells in Airway Basement Membrane (a) A. Cleaner B. Ammonia Exposure, Exposure, No. of No. of Cells/mm Cells/mm Small airways (epithelium) 1.8 1.9 (b) Small airways (subepithelium) 205.4 51.5 (b) Large airways (epithelium) 6.1 0.5 Large airways (subepithelium) 122.1 14.7 Obliterative Bronchiolitis C. Idiopathic, D. Idiopathic, No. of No. of Cells/mm Cells/mm Small airways (epithelium) 1.6 2.4 Small airways (subepithelium) 65.3 165.6 Large airways (epithelium) 0.6 NA (c) Large airways (subepithelium) 36.9 NA (c) E. F. G. H. Asthma, Asthma, Emphysema, Emphysema, No. of No. of No. of No. of Cells/mm Cells/mm Cells/mm Cells/mm Small airways (epithelium) 11.7 6.5 7.0 3.5 Small airways (subepithelium) 35.0 22.7 26.3 17.1 Large airways (epithelium) 10.4 14.5 17.5 13.2 Large airways (subepithelium) 49.8 64.0 32.7 19.1 (a) Staining in subepithelium of small airways is increased in obliterative bronchiolitis from household cleaner exposure (A) and ammonia exposure (B) and in idiopathic obliterative bronchiolitis (C and D) compared to staining in cases of asthma (E and F) and emphysema (G and H). (b) Reflects only involved airways (with fibrosis); see Table 3. (c) Posttransplantation wedge biopsy with no large airways available for examination. Table 2. Ratio of c-KIT (CD117)-Positive Mast Cells In Subepithelium and Epithelium in Small and Large Airways A. Cleaner B. Ammonia Exposure Exposure Subepithelium: epithelium in small airways 114.1:1 39.6:1 Subepithelium: epithelium in large airways 20.0:1 29.4:1 Obliterative Bronchiolitis C. D. Idiopathic Idiopathic Subepithelium: epithelium in small airways 40.8:1 69.0:1 Subepithelium: epithelium in large airways 61.5:1 NA E. F. G. H. Asthma Asthma Emphysem Emphysema Subepithelium: epithelium in small airways 3.0:1 3.5:1 3.8:1 4.9:1 Subepithelium: epithelium in large airways 4.8:1 4.4:1 1.9:1 1.4:1 Table 3. Comparison of c-KIT (CD117) Staining in Involved Small Airways (With Fibrosis) and Uninvolved Small Airways (Without Fibrosis) in a Case of Ammonia Exposure (a) Airways With Uninvolved Fibrosis (9), Airways (2), No. of Cells/mm No. of Cells/mm Small airway (epithelium) 1.9 0.2 Small airway (subepithelium) 51.5 13.8 (a) The data demonstrate an association between mast cells and fibrosis in a case of obliterative bronchiolitis from ammonia exposure (case B).
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|Author:||Fuehrer, Neil E.; Marchevsky, Alberto M.; Jagirdar, Jaishree|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Sep 1, 2009|
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