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As a respiratory disease with high morbidity and mortality, pulmonary fibrosis (PF) has been a serious threat to people's health. Hederagenin (HDG) is a pentacyclic triterpenoid saponin widely distributed in various plants. This study explored the role of HDG in Bleomycin (BLM)-induced PF and the molecular mechanism. The results showed that HDG reduced BLM-induced pulmonary dysfunction, pathological damage in a dose-dependent manner. Besides, HDG reduced BLM-induced collagen deposition by decreasing the levels of α-SMA, Collagen I and hydroxproline. Furthermore, HDG reduced the levels of inflammatory cytokines (TNF-α and IL-6), TGF-β1 and connective tissue growth factor (CTGF) in bronchoalveolar lavage fluid (BALF) or serum. Further mechanism analysis indicated that HDG inhibited the expression of Ras and phosphorylation of JNK and NFAT4 in a dose-dependent manner. However, the JNK pathway activator Anisomycin reversed this inhibitory effect. In conclusion, these findings suggest that HDG may be a potential target drug for PF therapy.

Background: Anti-C1q autoantibodies (autoAbs) are associated with systemic lupus erythematosus (SLE), but their presence in other rheumatic diseases has not been adequately investigated., Objectives: We aimed to assess anti-C1q autoAbs and circulating immune complexes (CICs) in systemic sclerosis (SSc)., Methods: In total 124 patients with SSc were studied; 106 were female and the median age was 59·4 years (range 25-81·4). Overall 75 (60·5%) had limited cutaneous SSc and 49 (39·5%) had diffuse cutaneous SSc. Also included were 25 patients with Sjögren syndrome (SjS), 29 with rheumatoid arthritis (RA), 38 with SLE and 53 healthy controls. Enzyme-linked immunosorbent assays with high- and low-salt buffers were used to measure anti-C1q antibodies and CICs. The former allows only anti-C1q antibody binding to C1q and the latter also allows IgG Fc to bind to C1q., Results: Anti-C1q antibodies were present in 20 of 124 (16·1%) patients with SSc: five had high levels (> 80 RU mL -1 ) and 10 (50%) had moderate levels (40-80 RU mL -1 ). Anti-C1q antibodies were also present in one of 25 (4%) patients with SjS, one of 29 (3%) with RA (P < 0·05 for both) and three of 53 (6%) healthy controls (P < 0·01). Anti-C1q antibodies were detected in 13 of 38 (34%) patients with SLEs. Anti-C1q antibodies were more frequent in male than female patients with SSc (P = 0·005); this association remained after multivariate regression analysis. Anti-C1q antibody level was the most important factor in predicting the presence of pulmonary fibrosis, and the second most important in predicting pulmonary arterial hypertension. Fourteen patients with SSc (11·3%) had CICs., Conclusions: Anti-C1q autoAbs were frequently detected in patients with SSc, and their high levels predict the co-occurrence of pulmonary fibrosis or pulmonary arterial hypertension., (© 2019 British Association of Dermatologists.)

Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P < 0.05). Hydroxyproline and GATA-3 expression were increased in the lung tissues of tumor-bearing mice following irradiation. CpG-ODN attenuated fibrosis by markedly decreasing GATA-3 expression. Serum IL-13 and IL-5 were elevated, whereas INF-γ and IL-12 expression were decreased in irradiated tumor-bearing mice. These changes were reversed after CpG-ODN treatment. Thus, Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD., Methods: Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease., Results: Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB., Conclusion: Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pulmonary fibrosis is associated with a number of disorders that affect the lung. Although there are several cellular types that are involved in the pathogenesis pulmonary fibrosis, the resident lung fibroblast has been viewed traditionally as the primary cell involved in promoting the deposition of ECM that culminates in pulmonary fibrosis. However, recent findings demonstrate that a circulating cell (i.e., the fibrocyte) can contribute to the evolution of pulmonary fibrosis. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of cell-surface markers related to leukocytes, hematopoietic progenitor cells, and fibroblasts. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. In this review, we present data supporting the critical role these cells play in the pathogenesis of pulmonary fibrosis.

Objective: To determine serum levels of soluble CD44 (sCD44), one of the adhesion molecules that regulate the migration of leucocytes, and clinical associations of these levels in patients with systemic sclerosis (SSc)., Methods: Serum sCD44 levels were examined by enzyme-linked immunosorbent assay., Results: Serum sCD44 levels were elevated in SSc patients compared with normal controls. Serum sCD44 levels were higher in patients with limited cutaneous SSc than in those with diffuse cutaneous SSc. Patients with elevated sCD44 levels had pulmonary fibrosis less frequently than those with normal sCD44 levels. Serum sCD44 levels remained elevated during the follow-up in almost all patients with elevated levels at their first visit, whereas they remained normal in all patients with normal levels., Conclusion: Elevated sCD44 levels were associated with a relatively mild subset of SSc. These results suggest that CD44 could be a potential therapeutic target in SSc.

Particulate matter air pollution (PM) has been associated with morbidity and mortality from ischemic heart disease and stroke in humans. It has been hypothesized that alveolar inflammation, resulting from exposure to PM, may induce a state of blood hypercoagulability, triggering cardiovascular events in susceptible individuals. Previous studies in our laboratory have demonstrated acute lung injury with alveolar inflammation in rats following exposure to residual oil fly ash (ROFA), an emission source particulate. In addition, increased mortality has been documented following exposure to ROFA in rats with preexistent cardiopulmonary disease. ROFA's toxicity derives from its soluble metal content, which appears also to drive the toxicity of ambient PM. The present study was conducted to test the hypothesis that exposure of rats to a toxic PM, like ROFA, would adversely alter hemostatic parameters and cardiovascular risk factors thought to be involved in human epidemiologic findings. Sixty-day-old male Sprague-Dawley rats were exposed by intratracheal instillation (IT) to varying doses (0.3, 1. 7, or 8.3 mg/kg) of ROFA, 8.3 mg/kg Mt. Saint Helen's volcanic ash (MSH, control particle), or 0.3 ml saline (SAL, control). At 24 h post-IT, activated partial thromboplastin time (APTT), prothrombin time (PT), plasma fibrinogen (PF), plasma viscosity (PV), and complete blood count (CBC) were performed on venous blood samples. No differences from control were detected in APTT and PT in ROFA-exposed rats; however, ROFA exposure did result in elevated PF, at 8.3 mg/kg only. In addition, PV values were elevated in both ROFA and MSH-exposed rats relative to SAL-control rats, but not significantly. Although no changes were detected in APTT and PT, alteration of important hematologic parameters (notably fibrinogen) through PM induction of an inflammatory response may serve as biomarkers of cardiovascular risk in susceptible individuals.

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine which has been reported to be important in the pathogenesis of rheumatoid arthritis (RA). In this study, the serum level of VEGF was measured using enzyme-linked immunosorbent assay in 17 patients with systemic lupus erythematosus, 49 patients with polymyositis/dermatomyositis (PM/DM), 40 patients with systemic lupus erythematosus, 49 patients with polymyositis/dermatomyositis (PM/DM), 40 patients with systemic sclerosis (SSc), 11 patients with RA and 20 control subjects. The VEGF level was 184 +/- 62 pg/mL (mean +/- SD) in the serum of normal individuals. The mean VEGF levels in the patients with PM/DM or RA were significantly higher than in the normal controls. In 21 of the 49 patients with PM/DM and nine of the 11 patients with RA, the serum VEGF level was considered to be elevated. In patients with SSc, those with diffuse cutaneous SSc showed elevated VEGF levels in comparison with normal controls. An elevated serum VEGF level was correlated with the frequency of lung fibrosis and reduced vital capacity in the patients with SSc.

Autoantibodies against DNA topoisomerase II alpha have been identified in the sera of patients with idiopathic pulmonary fibrosis (IPF). To map topoisomerase II autoepitopes, we tested by ELISA and immunoblotting the IPF anti-topoisomerase II-positive sera against a series of recombinant proteins which covered the full length of topoisomerase II alpha. Specific patterns of reactivity were observed, indicating the existence of multiple epitopes on topoisomerase II, either highly complex or conformational/discontiguous or conformational/contiguous ones. The latter resided in amino acid residues 854-1147 and 1370-1447. A detailed analysis of these regions was undertaken, but we were not able to pinpoint a sequential peptide-sized epitope, or any significant homology with foreign pathogens. Further, we observed a significant correlation between the progression from a contiguous to a quaternary/tertiary structure-dependent autoepitope and the disease duration but not with the disease severity. Therefore, this result supports the hypothesis that anti-topoisomerase II autoreactivity evolves following an antigen-driven process.

Objective: To determine the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) in patients with systemic sclerosis (SSc)., Method: Serum samples from 80 patients with SSc and 20 healthy control subjects were examined by a sensitive enzyme-linked immunosorbent assay., Results: The serum levels of sVCAM-1 and sE-selectin were significantly higher in the patients with SSc than in the healthy controls. The serum levels of sVCAM-1 were correlated with the presence of pulmonary fibrosis, joint involvement and elevated erythrocyte sedimentation rate levels. The serum levels of sE-selectin were correlated with the presence of pulmonary fibrosis., Conclusion: These results suggest that endothelial activation is involved in the development of this disease.

We have examined HLA-DR, DQA and DQB variants in 72 controls, 153 subjects with RA without extra-articular features and in subjects with the rheumatoid pulmonary complications of interstitial fibrosis (23) peripheral airways disease (13) and in 41 subjects with RA and bronchiectasis. Subjects with RA alone showed the expected association with HLA-DR4 (79%) but those with RA and co-existent pulmonary fibrosis were less likely to be DR4 positive (61%). No other HLA-DR variants were significantly increased in the different disease groups. HLA-DQB1*0501 which types serologically as DQw1 was increased in subjects with RA and peripheral airways disease as compared to rheumatoid subjects with normal lung function, but these differences were not statistically significant. DQB1*0601 was increased in subjects with bronchiectasis with or without RA (but only significantly so in RA-BR subjects) DQB1*0301, DQB1*0201 and DQA1*0501 frequencies were also increased in subjects with RA and bronchiectasis as compared to those with RA alone.

Macromolecular LD (lactate dehydrogenase, EC 1.1.1.27) was present in the serum of a patient suffering from idiopathic fibrosis of the lung and presenting signs of autoimmune disease. By using gel filtration and affinity chromatography techniques, the vast majority of the patient's serum LD activity was shown to consist of LD-IgG complexes, which dissociated in the presence of added nicotinamide adenine dinucleotide (NAD+). Binding studies with tritiated NAD+ indicated that complex formation was not ascribable to a lack of circulating cofactor. The most likely explanation for the complex formation was the existence of LD binding sites on IgG molecules. The disruption of the complex by NAD+ might be explained by a competition between IgG molecules and NAD+ for the LD active site or by conformational changes induced in the LD molecules on binding of NAD+.