The addition of oral iron improves chemotherapy-induced anemia in patients receiving erythropoiesis-stimulating agents.

Although many studies have shown that supplementation with iron and erythropoiesis-stimulating agents (ESA) is frequently used for managing chemotherapy-induced anemia (CIA), optimal combination therapy using these agents together to ameliorate anemia is not well characterized. To assess the effects of ESA combined with oral or intravenous (IV) iron on relieving CIA, PubMed, Cochrane Library, Embase and China National Knowledge Infrastructure (CNKI) were searched for articles. Data collected in the articles were meta-analyzed using RevMan 5.3 software with a random-effects model. Our comprehensive search yielded 1666 potentially relevant trials. A total of 41 trials randomizing 4200 patients with CIA fulfilled inclusion criteria, including 34 Chinese articles and 7 English articles. Meta-analysis showed that treatment with both ESA and iron more effectively improved CIA relative to iron supplementation alone, with increased hemoglobin, hematocrit, red blood cell count and hematopoietic response rate. Subgroup analyses revealed iron administration, both oral and IV iron, improved anemia in ESA-treated cancer patients with CIA. Our analysis demonstrates that iron supplementation combined with ESA more effectively ameliorates CIA relative to iron supplementation alone, without regard to whether IV or oral iron was used. Together, our findings may contribute to the clinical treatment of CIA using iron therapy with or without ESA.

Dihydrotanshinone I Alleviates Crystalline Silica-Induced Pulmonary Inflammation by Regulation of the Th Immune Response and Inhibition of STAT1/STAT3.

Occupational exposure to crystalline silica (CS) results in a persistent pulmonary inflammatory response that eventually leads to abnormal tissue repair, disability, and death. The inflammatory-immune responses occur in the early stages of CS exposure, and both innate and adaptive immunity are involved. CD4+ T cells play a pivotal role in the pathogenesis of CS-induced pulmonary disease, which has no proven curative therapy. Dihydrotanshinone I (DHI), a natural product isolated from Salvia miltiorrhiza Bunge (Danshen), has anti-inflammatory and immunomodulatory properties. However, whether DHI has a protective effect on CS-induced lung disease, how it influences the Th immune response, and the potential underlying molecular mechanism(s) have not been fully clarified. In this study, DHI treatment of CS-exposed mice reduced the expression of proinflammatory cytokines and the infiltration of immune cells. It significantly ameliorated CS-induced pulmonary inflammation by attenuating T helper (Th)1 and Th17 responses, which were tightly related to the inhibition of STAT1 and STAT3. DHI significantly altered Th2 cytokines but not the Th2 nuclear transcription factor. Furthermore, our study found that DHI treatment also affected regulatory T cell activity in CS-injured mice. Taken together, our findings indicated that DHI could modulate Th responses and alleviate CS-induced pulmonary inflammation, suggesting a novel application of DHI in CS-induced pulmonary disease.

Dioscin Alleviates Crystalline Silica-Induced Pulmonary Inflammation and Fibrosis through Promoting Alveolar Macrophage Autophagy.

Occupational exposure to crystalline silica (CS) particles leads to silicosis, which is characterized by chronic inflammation and abnormal tissue repair. Alveolar macrophages (AMs) play a crucial role in the process of silicosis. Previously, we demonstrated positive effect of dioscin on silicosis through modulating macrophage-elicited innate immune response. However, the concrete molecular mechanism remains to be discovered. Methods: We established experimental model of silicosis with wildtype and Atg5flox/floxDppa3Cre/+ mice and oral administrated dioscin daily to explore the effects of dioscin on macrophages and pulmonary fibrosis. AM cell line MH-S with Atg5 silence was used to explore specific function of dioscin on macrophage-derived inflammation and the underlying molecular mechanism. Results: Dioscin could promote autophagy in macrophages. Dioscin-triggered AMs autophagy limited mitochondrial reactive oxygen species (mtROS) mass stimulated by CS, reduced mitochondria-dependent apoptosis pathway activation and facilitated cell survival. Relieved oxidative stress resulted in decreased secretion of inflammatory factors and chemokines. Dioscin treatment alleviated macrophage-derived inflammation and subsequent abnormal collagen repair. All the dioscin's protective effects were diminished in Atg5flox/floxDppa3Cre/+ mice. Conclusion: Dioscin promoting autophagy leads to reduced CS-induced mitochondria-dependent apoptosis and cytokine production in AMs, which may provide concrete molecular mechanism for the therapy of silicosis.

4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice.

Silicosis is caused by exposure to crystalline silica (CS). We have previously shown that blocking 4-1BB signaling attenuated CS-induced inflammation and pulmonary fibrosis. However, the cells that express 4-1BB, which plays a vital role in promoting fibrosis, are still unknown. In this study, we demonstrated that the expression of 4-1BB is elevated in alveolar macrophages (AMs) in the lungs of CS-injured mice. CS exposure also markedly enhanced the expression of 4-1BB in macrophage-like, MH-S cells. In these cells, activation of the 4-1BB signaling with an agonist antibody led to upregulated secretion of pro-fibrotic mediators. Consistently, blocking 4-1BB downstream signaling or genetic deletion of 4-1BB alleviated pro-fibrotic responses in vitro, while treatment with a 4-1BB fusion protein promoted pro-fibrotic responses. In vivo experiments showed that blocking 4-1BB signaling decreased the expressions of pro-fibrotic mediators and fibrosis. These data suggest that 4-1BB signaling plays an important role in promoting AMs-mediated pro-fibrotic responses and pulmonary fibrosis. Our findings may provide a potential molecular target to reduce CS-induced fibrotic responses in occupational lung disease.

Dioscin Exerts Protective Effects Against Crystalline Silica-induced Pulmonary Fibrosis in Mice.

Inhalation of crystalline silica particles leads to pulmonary fibrosis, eventually resulting in respiratory failure and death. There are few effective drugs that can delay the progression of this disease; thus, patients with silicosis are usually only offered supportive care. Dioscin, a steroidal saponin, exhibits many biological activities and health benefits including its protective effects against hepatic fibrosis. However, the effect of dioscin on silicosis is unknown. METHODS: We employed experimental mouse mode of silicosis. Different doses of dioscin were gavaged to the animals 1 day after crystalline silica instillation to see the effect of dioscin on crystalline silica induced pulmonary fibrosis. Also, we used RAW264.7 and NIH-3T3 cell lines to explore dioscin effects on macrophages and fibroblasts. Dioscin was also oral treatment but 10 days after crystalline silica instillation to see its effect on established pulmonary fibrosis. RESULTS: Dioscin treatment reduced pro-inflammation and pro-fibrotic cytokine secretion by modulating innate and adaptive immune responses. It also reduced the recruitment of fibrocytes, protected epithelial cells from crystalline silica injury, inhibited transforming growth factor beta/Smad3 signaling and fibroblast activation. Together, these effects delayed the progression of crystalline silica-induced pulmonary fibrosis. The mechanism by which dioscin treatment alleviated CS-induced inflammation appeared to be via the reduction of macrophage, B lymphocyte, and T lymphocte infiltration into lung. Dioscin inhibits macrophages and fibroblasts from secreting pro-inflammatory cytokines and may also function as a modulator of T helper cells responses, concurrent with attenuated phosphorylation of the apoptosis signal-regulating kinase 1-p38/c-Jun N-terminal kinase pathway. Also, dioscin could block the phosphorylation of Smad3 in fibroblast. Oral treatment of dioscin could also effectively postpone the progression of established silicosis. CONCLUSION: Oral treatment dioscin delays crystalline silica-induced pulmonary fibrosis and exerts pulmonary protective effects in mice. Dioscin may be a novel and potent candidate for protection against crystalline silica-induced pulmonary fibrosis.

IL-10-Producing B Cells Regulate T Helper Cell Immune Responses during 1,3-ß-Glucan-Induced Lung Inflammation.

With the rapid development of industry and farm, fungi contamination widely exists in occupational environment. Inhalation of fungi-contaminated organic dust results in hypersensitivity pneumonitis. 1,3-ß-Glucan is a major cell wall component of fungus and is considered as a biomarker of fungi exposure. Current studies showed that 1,3-ß-glucan exposure induced lung inflammation, which involved uncontrolled T helper (Th) cell immune responses, such as Th1, Th2, Th17, and regulatory T cell (Treg). A recently identified IL-10-producing B cells (B10) was reported in regulating immune homeostasis. However, its regulatory role in hypersensitivity pneumonitis is still subject to debate. In our study, we comprehensively investigated the role of B10 and the relationship between B10 and Treg in 1,3-ß-glucan-induced lung inflammation. Mice with insufficient B10 exhibited more inflammatory cells accumulation and severer pathological inflammatory changes. Insufficient B10 led to increasing Th1, Th2, and Th17 responses and restricted Treg function. Depletion of Treg before the onset of inflammation could suppress B10. Whereas, Treg depletion only at the late stage of inflammation failed to affect B10. Our study demonstrated that insufficient B10 aggravated the lung inflammation mediated by dynamic shifts in Th immune responses after 1,3-ß-glucan exposure. The regulatory function of B10 on Th immune responses might be associated with Treg and IL-10. Treg could only interact with B10 at an early stage.

Blocking the 4-1BB Pathway Ameliorates Crystalline Silica-induced Lung Inflammation and Fibrosis in Mice.

Long term pulmonary exposure to crystalline silica leads to silicosis that manifests progressive interstitial fibrosis, eventually leading to respiratory failure and death. Despite efforts to eliminate silicosis, clinical cases continue to occur in both developing and developed countries. The exact mechanisms of crystalline silica-induced pulmonary fibrosis remain elusive. Herein, we find that 4-1BB is induced in response to crystalline silica injury in lungs and that it is highly expressed during development of experimental silicosis. Therefore, we explore the role of 4-1BB pathway during crystalline silica-induced lung injury and find that a specific inhibitor blocking the pathway could effectively alleviate crystalline silica-induced lung inflammation and subsequent pulmonary fibrosis in vivo. Compared to controls, the treated mice exhibited reduced Th1 and Th17 responses. The concentrations of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), including tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17A following crystalline silica challenge were also reduced in inhibitor-treated mice. Although there was no significant alteration in Th2 cytokines of IL-4 and IL-13, another type of pro-fibrogenic cell, regulatory T cell (Treg) was significantly affected. In addition, one of the major participants in fibrogenesis, fibrocyte recruited less due to the blockade. Furthermore, we demonstrated the decreased fibrocyte recruitment was associated with chemokine reductions in lung. Our study discovers the 4-1BB pathway signaling enhances inflammatory response and promotes pulmonary fibrosis induced by crystalline silica. The findings here provide novel insights into the molecular events that control crystalline silica-induced lung inflammation and fibrosis through regulating Th responses and the recruitment of fibrocytes in crystalline silica-exposed lung.

Blockade of Wnt/ß-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses.

CD4(+) T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/ß-catenin pathway could modulate the function and the differentiation of CD4(+) T cells. Therefore, Wnt/ß-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/ß-catenin pathway, we used lentivirus expressing ß-catenin shRNA to block the Wnt/ß-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4(+) T cells, we found that blockade of Wnt/ß-catenin pathway suppressed regulatory T cells (Tregs). Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/ß-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/ß-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/ß-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.