Bleomycin-induced Interstitial Pneumonia Research Articles

Effect of photodynamic therapy (PDT) on a rat model of bleomycin-induced interstitial pneumonia

BackgroundEven if lung cancer is detected at an early stage, surgery may be difficult in patients with severe comorbidities, like interstitial pneumonia (IP). Radiation therapy cannot be performed due to the high risk of acute IP exacerbation. Therefore, an effective alternative, such as photodynamic therapy (PDT), is required. To prove that acute exacerbation is not induced after PDT in peripheral lung cancer, we investigated the effects of PDT on IP rat models. MethodsBleomycin (BLM) was administered intratracheally. Seven days after administration, left thoracotomy was performed. Talaporfin sodium was injected, and diode laser irradiation (664 nm, 150mW, 100J/cm2) was performed. Seven days after PDT, the whole blood and left lungs were collected. A total of 23 rats, comprising BLM + PDT (n = 4), BLM + non-PDT (n = 10), non-BLM + PDT (n = 2), non-BLM + non-PDT (n = 5), and two rats that died immediately after PDT were observed. Serum levels of Krebs von den Lungen-6, surfactant protein-D, lactate dehydrogenase, and serum C-reactive protein were measured. Fibrosis and macrophage scorings, and the ​​collagen fibers percentage were examined by staining with hematoxylin and eosin, Elastica van Gieson, anti-α smooth muscle antibody, and anti-CD68 antibodies. ResultsThere was no remarkable difference in the values of each marker in fibrosis and macrophage scores with or without PDT. In case of death, fibrosis was mild, and PDT was not affected. ConclusionsIn IP rat models, PDT did not induce lung fibrosis or acute exacerbation.

Dexamethasone and lactoferrin induced PMN-MDSCs relieved inflammatory adverse events of anti-cancer therapy without tumor promotion

In this era of immune checkpoint inhibitors, inflammatory adverse events of anti-cancer therapies continue to pose a major challenge. Glucocorticoids, as the mainstay, were limited by serious side effects. Glucocorticoids induce myeloid-derived suppressor cells (MDSCs), and lactoferrin-induced polymorphonuclear MDSCs (PMN-MDSCs) were shown to relieve inflammatory conditions. Combined treatment with dexamethasone (DXM) and lactoferrin increased the generation of PMN-MDSCs in vitro (DXM/lactoferrin PMN-MDSCs) compared to DXM or lactoferrin treatment alone. DXM/lactoferrin PMN-MDSCs were distinct from tumor PMN-MDSCs in vivo with regard to gene expression profiles. DXM upregulated the myeloid cell response to lactoferrin by inducing the lactoferrin receptor Lrp1. DXM/lactoferrin PMN-MDSCs presented anti-bacterial capability, increased PGE2 production, increased survival capability, and decreased tumor tissue homing. Transfer of DXM/lactoferrin PMN-MDSCs relieved cisplatin-induced acute kidney failure, bleomycin-induced interstitial pneumonia, and allergic pneumonitis effectively without promoting tumor development. Our study shows that DXM/lactoferrin PMN-MDSCs are a promising cell therapy for inflammatory adverse events of anti-cancer therapies.

Identification of nine proteins in whole lung extract derived from bleomycin-induced interstitial pneumonia model mouse by two-dimensional electrophoresis/in-gel digestion/MALDI-TOF MSMS analysis

Identification of nine proteins in whole lung extract derived from bleomycin-induced interstitial pneumonia model mouse by two-dimensional electrophoresis/<i>in-gel</i> digestion/MALDI-TOF MSMS analysis

Effects of CX3CL1 inhibition on murine bleomycin-induced interstitial pneumonia

Background:Treatment for interstitial pneumonia (IP) associated with collagen diseases has not been established. There is a need to elucidate the pathogenesis of IP and develop a novel therapy. We aimed to clarify the role of chemokine (C-X3-C motif) ligand 1 (CX3CL1, also known as fractalkine) in IP.Methods:Bleomycin (BLM) was intratracheally administered to C57BL/6 mice to induce IP. For treatment with control Ab or anti-CX3CL1 mAb, the mice were administered either Ab three times per week for 2 weeks from the day of BLM administration until euthanasia. Expressions of CX3CL1 and its unique receptor CX3CR1 in the lung tissue were examined by immunohistochemical analysis. Cellular infiltration and lung fibrosis were evaluated based on hematoxylin-eosin-staining and Sirius red staining of the lung tissue sections, respectively. Bronchoalveolar lavage fluid (BALF) cells were analyzed by flow cytometry.Results:CX3CL1 and CX3CR1 were strongly expressed in the lung tissue from mice with BLM-induced IP (BLM-IP). Treatment with anti-CX3CL1 mAb did not significantly alter inflammatory cell infiltration or fibrosis in the lung tissue. However, the number of M1-like macrophages in BALF was decreased and surface CD3 expression on T cells was increased by anti-CX3CL1 mAb treatment.Conclusions:Inhibition of CX3CL1 decreased inflammatory cells and may attenuate T cell activation in BALF. CX3CL1 inhibitor may have the potential to suppress the infiltration and activation of immune cells in IP.

Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia

Adipose-derived stem cells (AdSCs) have recently been considered a useful treatment tool for autoimmune disease because of their anti-inflammatory and immunosuppressive effects. We investigated the therapeutic effect of intravenous AdSC transplantation in a mouse model of bleomycin-induced lung injury. AdSCs accumulated in the pulmonary interstitium and inhibited both inflammation and fibrosis in the lung, markedly improving the survival rate of mice with bleomycin-induced lung injury in a cell number-dependent manner. AdSCs inhibited the production of pro-inflammatory cytokines such as TNF-α and IL-12 in activated macrophages, and AdSCs also induced the apoptosis of activated macrophages. AdSCs inhibited the differentiation and proliferation of Th2-type mCD4+ T cells but promoted the differentiation and proliferation of regulatory T cells, suggesting that the phenotypic conversion of T cells may be one of the mechanisms for the anti-inflammatory effect of AdSCs on pulmonary fibrosis. These findings suggest that intravenous AdSCs could be a promising treatment for patients with interstitial pneumonia.

Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice.

Angiopoietin-like protein 2 (ANGPTL2) is a chronic inflammatory mediator that, when deregulated, is associated with various pathologies. However, little is known about its activity in lung. To assess a possible lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse ANGPTL2 and then evaluated protein expression in mouse lung tissue. We observed abundant ANGPTL2 expression in both alveolar epithelial type I and type II cells and in resident alveolar macrophages under normal conditions. To assess ANGPTL2 function, we compared lung phenotypes in Angptl2 knockout (KO) and wild-type mice but observed no overt changes. We then generated a bleomycin-induced interstitial pneumonia model using wild-type and Angptl2 KO mice. Bleomycin-treated wild-type mice showed specifically upregulated ANGPTL2 expression in areas of severe fibrosing interstitial pneumonia, while Angptl2 KO mice developed more severe lung fibrosis than did comparably treated wild-type mice. Lung fibrosis seen following bone marrow transplant was comparable in wild-type or Angptl2 KO mice treated with bleomycin, suggesting that Angptl2 loss in myeloid cells does not underlie fibrotic phenotypes. We conclude that Angptl2 deficiency in lung epithelial cells and resident alveolar macrophages causes severe lung fibrosis seen following bleomycin treatment, suggesting that ANGPTL2 derived from these cell types plays a protective role against fibrosis in lung.

Post-chemotherapy Laparoscopic Retroperitoneal Lymph-Node Dissection in Testis Cancer Patients

Retroperitoneal lymph node dissection (RPLND) is still the most sensitive and specific method for the detection of malignant tumor and mature teratoma in stage II nonseminomatous testicular carcinoma after chemotherapy. Acceptance of this operation, however, has decreased because of the morbidity associated with the open approach. To reduce the morbidity and to improve the acceptance of RPLND, laparoscopy has been introduced. In this study, we describe our experiences with laparoscopic RPLND for stage II testicular carcinoma after chemotherapy. Sixteen patients underwent 17 laparoscopic RPLND after chemotherapy for clinical stage IIA-III nonseminomatous testicular cancer. Patients with post-chemotherapy residual masses >1 cm and normalization of tumor markers were considered for the procedure. Our dissection field included the resection of the residual tumor as well as the ipsilateral template. Laparoscopic RPLND was completed in all patients. Operative time ranged from 125 to 370 minutes (mean 240 +/- 56 min). No transfusions were required, and no intra- or postoperative complications occurred because of the procedure. A bleomycin-induced interstitial pneumonia developed in one patient. After a mean follow-up period of 26 +/- 11 months (range 4 to 38), two disease recurrences were observed. Laparoscopic RPLND after chemotherapy is a feasible and oncologically safe procedure. However, the technique is challenging and should only be performed in selected patients with low residual tumor volume.

Production of Superoxide and Nitric Oxide by Alveolar Macrophages in the Bleomycin-Induced Interstitial Pneumonia Mice Model

To elucidate the potential role of superoxide (O2−) and nitric oxide (NO) in the pathogenesis of interstitial pneumonia, the quantity of O2− and NO produced by the alveolar macrophages (AM) were determined in the bleomycin (BLM)-induced interstitial pneumonia mouse model. The production of O2− and NO increased on days 7, 14 and 21 after BLM injection. Strong expression of peroxynitrite (ONOO−) was seen in AM by using immunostaining for nitrotyrosine. The hydroxyproline contents increased on day 21 after BLM injection. O2− and NO are thought to play an important role in the pathology of fibrosis.

Bleomycin-induced interstitial pneumonia in dogs.

The intravenous administration of Bleomycin to 10 dogs at different dosages resulted in varying degrees of interstitial pneumonia in all cases and a lower incidence of nephrosis, foot pad excoriation and ulceration, onychoptosis, and alopecia. Pulmonary changes did not occur as a simple dose-related phenomenon. The lesions required at least 38 days to become apparent and appeared to increase in severity with time. Even at the lowest dose used (0·625 mg/kg body weight) very severe changes were seen 128 days after cessation of therapy. Morphological features of interstitial pneumonia were subpleural localization, focal mesothelial hyperplasia, marked hyperplasia and metaplasia of type II pneumocytes, fetalization of alveoli, and a pleomorphic inflammatory infiltrate. In cross-sections of lung lobes selected for histology approximately 1 to 22% of the parenchyma contained lesions. Involved areas showed marked elastosis, excess of reticular fibres, fibrosis, and increased acid mucopolysaccharides. The administration of Bleomycin produced pulmonary changes similar in many respects to those reported in busulphan-treated patients and desquamative interstitial pneumonia. The finding of interstitial pneumonia and pulmonary fibrosis in dogs treated with low doses over prolonged periods points the need to monitor pulmonary function in humans treated with Bleomycin.