High Concentrations of Soluble Fas Ligand in Bronchoalveolar Lavage Fluid of Patients with Pulmonary Sarcoidosis

Shikuwa, Chieko; Kadota, Jun‐ichi; Mukae, Hiroshi; Iwashita, Tetsuji; Kaida, Hideyuki; Ishii, Hiroshi; Ishimatsu, Yuji; Kohno, Shigeru

doi:10.1159/000063627

Cited by 13 publications

(8 citation statements)

References 21 publications

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“…In fact, the presence of elevated levels of the anti-apoptotic protein soluble Fas in the serum and its message in peripheral blood mononuclear cells from silicosis patients (Otsuki et al, 2000) indicates that the granuloma formation in human silicosis may not be associated with apoptotic cell death. The presence of anti-apoptotic factors, including soluble Fas and soluble Fas ligand, was also found in other fibrotic/granulomatous human lung diseases, including tuberculosis, sarcoidosis, and pulmonary fibrosis (Kuwano et al, 2000; Ordway et al, 2005; Shikuwa et al, 2002). Moreover, the results from other proliferative diseases suggest that apoptosis is associated with improvement in the disease.…”

Section: Discussionmentioning

confidence: 87%

Granuloma Formation Induced by Low-Dose Chronic Silica Inhalation is Associated with an Anti-Apoptotic Response in Lewis Rats

Mishra

Peña-Philippides

Hutt

et al. 2010

Journal of Toxicology and Environmental Health, Part A

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Chronic human silicosis results primarily from continued occupational exposure to silica and exhibits a long asymptomatic latency. Similarly, continued exposure of Lewis rats to low doses of silica is known to cause delayed granuloma formation with limited lung inflammation and injury. On the other hand, intratracheal exposure to large doses of silica induces acute silicosis characterized by granuloma-like formations in the lung associated with apoptosis, severe alveolitis, and alveolar lipoproteinosis. To ascertain similarities/differences between acute and chronic silicosis, in this communication, we compared cellular and molecular changes in established rat models of acute and chronic silicosis. In Lewis rats, acute silicosis was induced by intratracheal instillation of 35 mg silica, and chronic silicosis through inhalation of aerosolized silica (6.2 mg/m 3 , 5 days/week for 6 weeks). Animals exposed to acute high-dose silica were sacrificed at 14 days after silica instillation while chronically silica-treated animals were sacrificed between 4 days and 28 wk after silica exposure. The lung granulomas formation in acute silicosis was associated with strong inflammation, presence of TUNEL-positive cells and increases in caspase-3 activity and other molecular markers of apoptosis. On the other hand, lungs from chronically silica-exposed animals exhibited limited inflammation and increased expression of anti-apoptotic markers, including dramatic increases in Bcl-2 and procaspase-3, and lower caspase-3 activity. Moreover, chronic silicotic lungs were TUNEL-negative and overexpressed Bcl-3 and NF-κB-p50 but not NF-κB-p65 subunits. These results suggest that, unlike acute silicosis, chronic exposures to occupationally relevant doses of silica causes significantly lower lung inflammation and elevated expression of anti-apoptotic rather than proapoptotic markers in the lung that might result from interaction between NF-κB-p50 and Bcl-3. Keywords silicosis; apoptosis; lung inflammation; granuloma Epidemiological studies indicate that chronic silicosis is generally associated with occupational exposure to crystalline silica and is mostly prevalent in stone dressers, and quarry and foundry workers Chong et al., 2006;Hnizdo and Vallyathan, 2003). Depending on the dose, silica may produce acute (accelerated silicosis) or various forms of chronic silicosis (Borges et al., 2002;Castranova et al., 2002;Chong et al., 2006; Hnizdo and Vallyathan, * These studies were supported in part by grants from NIH (R01 DA017003, R01 DA04208-15, and R01DA04208) and from the U.S. 2003;Langley et al., 2004;Shi et al., 1998;McLaughlin et al., 1997). Although in animals, both high-dose acute and low-dose chronic silica exposures induce granulomatous changes in the lung, the granuloma-like structures formed in acute silicosis are a loose aggregate of activated foamy histiocytes and lymphocytes. On the other hand, the granulomas in chronic silicosis in both humans (Hnizdo and Vallyathan, 2003) and animals (Langley et al., 2004) are disc...

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Section: Discussionmentioning

confidence: 87%

Granuloma Formation Induced by Low-Dose Chronic Silica Inhalation is Associated with an Anti-Apoptotic Response in Lewis Rats

Mishra

Peña-Philippides

Hutt

et al. 2010

Journal of Toxicology and Environmental Health, Part A

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“…XAF1 is a negative regulator of XIAP, upregulating apoptosis by antagonizing the anti-caspase activity of XIAP [21]. XAF1 also antagonizes the cellular inhibitor of apoptosis genes C-IAP1 and C-IAP2 [22], and may sensitize cells to Fas-mediated apoptosis [23], which is thought to play a role in sarcoidosis [24], [25]. In IHC expression studies, we observed lack of XAF1 expression in sarcoidosis affected tissues and higher XIAP expression within sarcoid granulomas than in surrounding tissues.…”

Section: Discussionmentioning

confidence: 99%

Admixture Fine-Mapping in African Americans Implicates XAF1 as a Possible Sarcoidosis Risk Gene

et al. 2014

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Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions—6p24.3–p12.1, 17p13.3–13.1, 2p13.3–q12.1, and 6q23.3–q25.2—in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3–p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10−11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3–13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10−6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.

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“…Dai et al [10] observed the presence of increased apoptotic signaling receptors in BALF macrophages (increased expression of Fas receptor and tumor necrosis factor receptor 1) in patients with active sarcoidosis. Shikuwa et al [23] found high concentrations of soluble Fas ligand in BALF of patients with pulmonary sarcoidosis. On the other hand, Stridh et al [24] found that BALF lymphocytes from patients with active sarcoidosis display a nonapoptotic morphology associated with endogenous caspase 3 activity.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Bcl-2 Protein in Bronchoalveolar Lavage Lymphocytes and Macrophages in Sarcoidosis

Mermigkis

Polychronopoulos²,

Mermigkis³

et al. 2006

Respiration

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Background and Objectives: Apoptosis, also known as programmed cell death, probably correlates with the pathophysiologic mechanisms of alveolitis in sarcoidosis. Our purpose was to investigate any changes in the expression of the antiapoptotic protein Bcl-2, one of the most important inhibiting factors of apoptosis, in bronchoalveolar lavage fluid (BALF) cell populations in patients with sarcoidosis. Subjects and Methods: Fiberoptic bronchoscopy with BAL was performed in 13 patients with active sarcoidosis (10 patients with stage I and 3 with stage II disease based on chest radiography). None of them was under treatment with corticosteroids. Cellular Bcl-2 expression was identified using an immunoperoxidase staining method. Ten normal subjects served as control group. Results: BALF lymphocytes and macrophages in sarcoid patients exhibited a significant increase in the expression of Bcl-2 compared with the control group (p < 0.001). A Bcl-2 expression of 80.7 ± 8.5% in the lymphocytes and 77.4 ± 8.9% in the macrophages was observed in sarcoidosis versus 32.2 ± 13.8% and 19.6% ± 7.6% in normal subjects, respectively. The percentages of Bcl-2 expression in the lymphocytes were positively correlated with BALF CD4/CD8 ratio values (p = 0.02, r = 0.63). Conclusions: Our results suggest that the antiapoptotic protein Bcl-2 is overexpressed in alveolar lymphocytes and macrophages, which characterize the alveolitis in sarcoidosis and could provide insights into the pathogenesis of the disease and prove useful as a marker of disease activity or response to therapy.

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High Concentrations of Soluble Fas Ligand in Bronchoalveolar Lavage Fluid of Patients with Pulmonary Sarcoidosis

Cited by 13 publications

References 21 publications

Granuloma Formation Induced by Low-Dose Chronic Silica Inhalation is Associated with an Anti-Apoptotic Response in Lewis Rats

Granuloma Formation Induced by Low-Dose Chronic Silica Inhalation is Associated with an Anti-Apoptotic Response in Lewis Rats

Admixture Fine-Mapping in African Americans Implicates XAF1 as a Possible Sarcoidosis Risk Gene

Overexpression of Bcl-2 Protein in Bronchoalveolar Lavage Lymphocytes and Macrophages in Sarcoidosis

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