Forsythiaside A ameliorates bleomycin-induced pulmonary fibrosis by inhibiting oxidative stress and apoptosis.

BACKGROUND: Pulmonary fibrosis (PF) is a common clinically critical disease characterized by high morbidity and high mortality. Forsythiaside A (FA) is a phenylethanol glycoside component in Forsythia suspensa, which has anti-inflammatory, antioxidant, and antiviral activities. However, the effects of FA on bleomycin (BLM)-induced PF are unclear. PURPOSE: The present study explored the role of FA in the amelioration of oxidative stress and apoptosis in BLM-induced PF as well as the possible underlying mechanisms, in vivo and in vitro. METHODS: Network pharmacology was used to collect the effects of FA on BLM-induced PF. Subsequently, further observation of the effects of FA on mice with PF by pulmonary pathological changes, transmission electron microscopy, real-time polymerase chain reaction, Western blot analysis, immunofluorescence, and immunohistochemistry. An in vitro model was constructed by inducing A549 with transforming growth factor beta-1 (TGF-ß1) to observe the effect of FA on epithelial cell apoptosis. RESULTS: Network pharmacology predicted signaling pathways such as IL-17 signaling pathway and Relaxin signaling pathway. The results of in vivo studies showed that FA ameliorated BLM-induced PF through inhibition of fibrosis, modulation of apoptosis, and oxidative stress. In addition, FA promoted TGF-ß1-induced apoptosis in A549 cells. CONCLUSIONS: The results of our study suggested that FA could protect mice against BLM-induced PF by regulating oxidative stress and apoptosis as well as the Epithelial mesenchymal transition pathway.

PF127/bleomycin hydrogel promotes subcutaneous extracellular matrix remodeling and fibrosis to construct personalized flaps through the TGFß-Col signaling pathway.

BACKGROUND: Skin flap transplantation is used to effectively reconstruct defects of the hand and foot skin and soft tissues. We here investigated the effect of the PF127/bleomycin (BLM) hydrogel on the extracellular matrix (ECM) remodeling of skin flaps and the underlying mechanism, thereby providing a new reference point for personalized flap modification and overcoming abrasion resistance- and stability-associated difficulties. METHODS: The appropriate PF127/BLM concentration was selected based on the gelation time and drug release curve. Migration assays, scratch assays, and live/dead staining were conducted to verify the effect of PF127/BLM on human skin fibroblasts (HSFs). The effects of PF127/BLM on the ECM were assessed through hematoxylin and eosin and Masson staining. Additionally, we examined the expression of ECM remodeling-related genes and proteins involved in their associated signaling pathway. Finally, the effects of PF127/BLM on organ fibrosis and toxicity to liver and kidney functions were assessed in mice. RESULTS: A 25% PF127/BLM hydrogel was selected as the study concentration. PF127/BLM augmented HSF chemotaxis and proliferation. Furthermore, PF127/BLM promoted subcutaneous ECM remodeling and fibrosis, increased the flap dermis thickness, and reduced the toxic side effects of BLM on liver/lung fibrosis and liver/kidney function. Additional studies confirmed that the PF127/BLM-mediated regulation of ECM remodeling in skin flaps was associated with TGFß-Col signaling pathway activation. CONCLUSION: The PF127/BLM hydrogel promoted subcutaneous ECM remodeling and fibrosis, which aided the construction of personalized flaps through the TGFß-Col signaling pathway, with decreased hepatic, pulmonary, and renal toxicities.

Percutaneous treatment of lumbar synovial cysts with bleomycin: A case report.

Lumbar synovial cysts (LSC) that protrude into the spinal canal can cause lower back pain, neurogenic claudication, and radiculopathy. Often diagnosed in the elderly population (typically ∼60 years of age) with a slight preponderance for females, their underlying etiology is thought to be due to degeneration of the adjacent facet joint, with the most common location at the level of L4-L5. Treatment of LSC can be conservative (with NSAIDs and physical therapy), percutaneous (with rupture), or surgically (with decompression with or without fusion). Percutaneous treatment of LSC involves rupturing the cyst by injecting it with steroids and local anesthetics. Although this option is less invasive than surgery, multiple studies have documented recurrence with this method and patients eventually undergoing surgical intervention. In this report, we document a case where a patient who presented with a symptomatic LSC underwent successful percutaneous treatment with bleomycin.

Tuberostemonine may alleviates proliferation of lung fibroblasts caused by pulmonary fibrosis.

OBJECTIVES: Tuberostemonine has several biological activity, the aim of study examined the impact of tuberostemonine on the proliferation of TGF-ß1 induced cell model, and its ability to alleviate pulmonary fibrosis stimulated by bleomycin in mice. METHODS: In vitro, we assessed the effect of tuberostemonine (350, 550 and 750 µM) on the proliferation of cells stimulated by TGF-ß1 (10 µg/L), as well as on parameters such as α-SMA vitality, human fibronectin, collagen, and hydroxyproline levels in cells. In vivo, we analyzed inflammation, hydroxyproline, collagen activity and metabolomics in the lungs of mice. Additionally, a comprehensive investigation into the TGF-ß/smad signaling pathway was undertaken, targeting lung tissue as well as HFL cells. RESULTS: Within the confines of an in vitro setup, the tuberostemonine manifested a discerned IC50 of 1.9 mM. Furthermore, a significant reduction of over fifty percent was ascertained in the secretion levels of hydroxyproline, fibronectin, collagen type I, collagen type III and α-SMA. In vivo, tuberostemonine obviously improved the respiratory function percentage over 50% of animal model and decreased the hydroxyproline, lung inflammation and collagen deposition. A prominent decline in TGF-ß/smad pathway functioning was identified within both the internal and external cellular contexts. CONCLUSIONS: Tuberostemonine is considered as a modulator to alleviate fibrosis and may become a new renovation for pulmonary fibrosis.

Chemoreflex sensitization occurs in both male and female rats during recovery from acute lung injury.

Introduction: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI. Methods: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. Results: There were no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1 mth post-bleo. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats. Both male and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes. Conclusion: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders.

Therapeutic use of fisetin and pirfenidone combination in bleomycin-induced pulmonary fibrosis in adult male albino rats.

Pulmonary fibrosis is an important health problem; one of the drugs used in its treatment is pirfenidone (PFD). Fisetin (FST) is a flavonoid with antioxidative, anti-inflammatory, and antifibrotic effects. The aim of this study was to induce PF in rats with bleomycin (BLM) and to investigate the combined effect of PFD and FST in the treatment of fibrosis. In the study, 40 male Wistar rats were divided into five groups (n = 8). Sham group was administered saline on day 0 and BLM (5 mg/kg, i.t.) was administered to the other groups; BLM + PFD group: PFD (50 mg/kg) was administered every day between the first and 15th days; BLM + FST group: FST (25 mg/kg) was administered between the first and 15th days; BLM + PFD + FST group: PFD (50 mg/kg) and FST (25 mg/kg) were administered by gavage every day between the first and 15th days. At the end of the 15th day, BAL was performed under anaesthesia and lung tissues were removed. Histopathological, biochemical, and RT-PCR analyses were performed in the lung tissue. In our study, the concomitant use of FST and PFD caused downregulation of NF-κB p65, TGF-ß1, and α-SMA expressions; downregulation of TIMP-1, MMP-2, and MMP-9 genes; downregulation of HYP, MPO, and MDA activity; decrease in the number of differential cells in BAL; and upregulation of GSH. This shows that FST and PFD have antifibrotic, antioxidative, and anti-inflammatory effects. Our results show that the combined use of PFD and FST in BLM-induced pulmonary fibrosis reduces extracellular matrix accumulation, downregulates the level of gelatinases and their inhibitors, and provides significant improvements in antioxidative defence parameters.

Epithelial-mesenchymal transition in chemoradiation-induced lung damage: Mechanisms and potential treatment approaches.

Pulmonary injury is one of the key restricting factors for the therapy of malignancies with chemotherapy or following radiotherapy for chest cancers. The lung is a sensitive organ to some severely toxic antitumor drugs, consisting of bleomycin and alkylating agents. Furthermore, treatment with radiotherapy may drive acute and late adverse impacts on the lung. The major consequences of radiotherapy and chemotherapy in the lung are pneumonitis and fibrosis. Pneumonitis may arise some months to a few years behind cancer therapy. However, fibrosis is a long-term effect that appears years after chemo/or radiotherapy. Several mechanisms such as oxidative stress and severe immune reactions are implicated in the progression of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) is offered as a pivotal mechanism for lung fibrosis behind chemotherapy and radiotherapy. It seems that pulmonary fibrosis is the main consequence of EMT after chemo/radiotherapy. Several biological processes, consisting of the liberation of pro-inflammatory and pro-fibrosis molecules, oxidative stress, upregulation of nuclear factor of κB and Akt, epigenetic changes, and some others, may participate in EMT and pulmonary fibrosis behind cancer therapy. In this review, we aim to discuss how chemotherapy or radiotherapy may promote EMT and lung fibrosis. Furthermore, we review potential targets and effective agents to suppress EMT and lung fibrosis after cancer therapy.

Pirfenidone Alleviates Inflammation and Fibrosis of Acute Respiratory Distress Syndrome by Modulating the Transforming Growth Factor-ß/Smad Signaling Pathway.

Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-ß1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-ß1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.

Screen-Printed Electrodes-A Promising Tool for Antineoplastic Drug Detection (Cisplatin and Bleomycin) in Biological Samples.

Cancer remains one of the leading causes for death worldwide. Palliative chemotherapy is vital for certain cancer patients, highlighting the critical need for treatment monitoring tools to prevent drug accumulation and mitigate the risk of high toxicity. Therefore, our aim was to evaluate the potential of screen-printed electrodes for the development of sensitive and accurate biosensors for the detection/quantification of antineoplastic drugs. To this purpose, we developed a cisplatin sensor. By functionalizing the gold electrode with human serum albumin and by collecting the electrochemical signal obtained in a H2O2 solution, through voltammetry measurements, we were able to correlate the current measured at 430 mV with the concentration of cisplatin present in human serum samples, with a correlation coefficient of R2 = 0.99. Also, a bleomycin biosensor was developed and proven functional, but further optimization steps were employed in order to improve the accuracy. The developed biosensors have a detection range of 0.0006-43.2 mg/mL for cisplatin and 0.23-7.56 µg/mL for bleomycin in the serum samples. Our preliminary results show that these biosensors can facilitate the real-time monitoring of cisplatin and bleomycin serum levels, allowing healthcare professionals to tailor treatment strategies based on individual patient responses.

Carvacrol protects rats against bleomycin-induced lung oxidative stress, inflammation, and fibrosis.

The main objective of this study was to investigate the potential efficacy of carvacrol (CAR) in mitigating bleomycin (BLM)-induced pulmonary fibrosis (PF). Sixty-six male Wistar rats were assigned into two main groups of 7 and 21 days. They were divided into the subgroups of control, BLM, CAR 80 (only for the 21-day group), and CAR treatment groups. The CAR treatment groups received CAR (20, 40, and 80 mg/kg, orally) for 7 or 21 days after an instillation of BLM (5 mg/kg, intratracheally). Results indicated that BLM significantly increased total cell count in bronchoalveolar lavage fluid and the percentages of neutrophils and lymphocytes, and reduced the percentage of macrophages. CAR dose-dependently decreased total cell count and the percentage of neutrophils and lymphocytes. CAR significantly reduced thiobarbituric acid reactive substances and hydroxyproline levels and elevated the total thiol level and catalase, superoxide dismutase, and glutathione peroxidase activities in BLM-exposed rats. Furthermore, CAR decreased the transforming growth factor-ß1, connective transforming growth factor, and tumor necrosis factor-α on days 7 and 21. BLM increased interferon-γ on day 7 but decreased its level on day 21. However, CAR reversed interferon-γ levels on days 7 and 21. Based on histopathological findings, BLM induced inflammation on days 7 and 21, but for induction of fibrosis, 21-day study showed more fibrotic injuries than the 7-day group. CAR showed the improvement of fibrotic injuries. The effect of CAR against BLM-induced pulmonary fibrosis is possibly due to its antioxidant, anti-inflammatory, and antifibrotic activity.

Case report: a cataract induced by bleomycin in a patient with testicular cancer.

Background: Bleomycin is a glycopeptide antibiotic with outstanding anti-tumor effects. A major adverse effect of bleomycin is lung fibrosis. However, the development of cataracts as a severe adverse effect has not been reported. Case summary: Herein, we describe the first case of cataract induced by bleomycin therapy in a 22-year-old male with testicular cancer. After surgical intervention and following five successive chemotherapy cycles of the BEP regimen, including bleomycin, etoposide and cisplatin, the patient reported a gradual painless loss of vision, with substantial decline in visual ability, especially in the right eye. Following comprehensive eye examinations, a cataract was diagnosed. Eventually, the patient underwent phacoemulsification and received replacement of the intraocular lenses. Conclusion: Bleomycin can cause cataracts, which induces a significant loss of vision. Therefore, clinicians should observe early symptoms and properly adjust treatment to prevent aggravation of symptoms.

Combined CO2 Laser Vaporization and Bleomycin Injection to Treat Huge Adult Laryngeal Vascular Anomalies: Innovative Application of CO2 Laser in Otolaryngology.

OBJECTIVES: The aim of this study was to assess the value of CO2 laser vaporization in treating huge adult laryngeal vascular anomalies (HALVAs) by combining it with bleomycin injection. MATERIALS AND METHODS: This study retrospectively reviewed the records of 13 adult patients who underwent 18 different procedures. Methods to treat HALVAs include traditional bleomycin injection and CO2 laser vaporization combined with bleomycin injection between September 2009 and January 2023. Treatment results were evaluated by the grade of lumen constriction. RESULTS: A total of five males and eight females, with an average age of 46.3 years (range, 22-66 years), were included in the study. The huge adult laryngeal vascular anomalies in our study were greater than 1633.71 mm3, and the long diameters of the bases were longer than 15 mm. Compared with the bleomycin injection-only group, the results with the CO2 laser vaporization and bleomycin injection combined were better. CONCLUSIONS: Both bleomycin injection and CO2 laser vaporization are safe treatment methods. Their combination may produce better results for huge adult laryngeal vascular anomalies.

Electroporation with Calcium or Bleomycin: First Application in an In Vivo Uveal Melanoma Patient-Derived Xenograft Model.

Uveal melanoma (UM) represents a rare tumor of the uveal tract and is associated with a poor prognosis due to the high risk of metastasis. Despite advances in the treatment of UM, the mortality rate remains high, dictating an urgent need for novel therapeutic strategies. The current study introduces the first in vivo analysis of the therapeutic potential of calcium electroporation (CaEP) compared with electrochemotherapy (ECT) with bleomycin in a patient-derived xenograft (PDX) model based on the chorioallantoic membrane (CAM) assay. The experiments were conducted as monotherapy with either 5 or 10 mM calcium chloride or 1 or 2.5 µg/mL bleomycin in combination with EP or EP alone. CaEP and ECT induced a similar reduction in proliferative activity, neovascularization, and melanocytic expansion. A dose-dependent effect of CaEP triggered a significant induction of necrosis, whereas ECT application of 1 µg/mL bleomycin resulted in a significantly increased apoptotic response compared with untreated tumor grafts. Our results outline the prospective use of CaEP and ECT with bleomycin as an adjuvant treatment of UM, facilitating adequate local tumor control and potentially an improvement in metastatic and overall survival rates.

Targeted delivery of TGF-ß mRNA to lung parenchyma using one-component ionizable amphiphilic Janus Dendrimers.

Current clinical strategies for the delivery of pulmonary therapeutics to the lung are primarily targeted to the upper portions of the airways. However, targeted delivery to the lower regions of the lung is necessary for the treatment of parenchymal lung injury and disease. Here, we have developed an mRNA therapeutic for the lower lung using one-component Ionizable Amphiphilic Janus Dendrimers (IAJDs) as a delivery vehicle. We deliver an anti-inflammatory cytokine mRNA, transforming growth factor-beta (TGF-ß), to produce transient protein expression in the lower regions of the lung. This study highlights IAJD's potential for precise, effective, and safe delivery of TGF-ß mRNA to the lung. This delivery system offers a promising approach for targeting therapeutics to the specific tissues, a strategy necessary to fill the current clinical gap in treating parenchymal lung injury and disease.

Sclerotherapy for the intraoral ranula with bleomycin: technical considerations and preliminary experience.

Ranula is a mucous cyst that occurs in the sublingual gland (SLG) in the floor of the mouth. It can be classified into two types based on origins: One is the the lesser sublingual gland (LSLG) in the anterior segment and the Rivini duct, which is connected to it, and the other is the greater sublingual gland (GSLG) in the posterior segment. Because of the anatomical characteristics, surgical resection of the cysts carries the risk of damaging adjacent tissues and has a high recurrence rate. Intralesional injection of sclerotherapy may be a better alternative treatment. We summarized 65 cases of ranula treated with intralesional injections of bleomycin(BML). According to the origin of the ranula, 60 cases were from the LSLG and the Rivini duct, and 5 cases were from the GSLG. The results showed that 60 cases of ranula from LSLG and Rivini ducts were 100% cured during the follow-up period. The median number of injections for all patients was 1.16. All 5 cases of ranula from the GSLG did not wholly recover. This study confirmed that BLM intralesional injection is a safe and effective treatment modality for cysts from LSLG or the ducts of Rivini rather than GSLG. Therefore, before treatment, it is necessary to determine the type and origin of the cyst by characterizing its morphology to ensure the effectiveness of the treatment.

Wogonin protects against bleomycin-induced mouse pulmonary fibrosis via the inhibition of CDK9/p53-mediated cell senescence.

Pulmonary fibrosis (PF) is a fatal interstitial lung disease associated with declining pulmonary function but currently with few effective drugs. Cellular senescence has been implicated in the pathogenesis of PF and could be a potential therapeutic target. Emerging evidence suggests wogonin, the bioactive compound isolated from Scutellaria baicalensis, owns the anti-senescence properties, however, the possible impact of wogonin on PF and the potential mechanisms remain unclear. In this study, a well-established mouse model of PF was utilized which mice were administrated with bleomycin (BLM). Strikingly, wogonin treatment significantly reduced fibrosis deposition in the lung induced by BLM. In vitro, wogonin also suppressed fibrotic markers of cultured epithelial cells stimulated by BLM or hydrogen peroxide. Mechanistic investigation revealed that wogonin attenuated the expressions of DNA damage marker γ-H2AX and senescence-related markers including phosphorylated p53, p21, retinoblastoma protein (pRB), and senescence-associated ß-galactosidase (SA-ß-gal). Moreover, wogonin, as a direct and selective inhibitor of cyclin-dependent kinase 9 (CDK9), exhibited anti-fibrotic capacity by inhibiting CDK9 and p53/p21 signalling. In conclusion, wogonin protects against BLM-induced PF in mice through the inhibition of cell senescence via the regulation of CDK9/p53 and DNA damage pathway. This is the first study to demonstrate the beneficial effect of wogonin on PF, and its implication as a novel candidate for PF therapy.

Electrochemotherapy with intravenous, intratumoral, or combined administration of bleomycin in the treatment of colorectal hepatic metastases in a rat model.

Electrochemotherapy (ECT) combines the reversible electroporation (rEP) with intravenous (i.v.) or intratumoral (i.t.) administration of chemotherapeutic drugs. We conducted this study to compare the efficacy of i.v., i.t., and i.v. + i.t. injection of bleomycin (BLM) in ECT treatment of colorectal hepatic metastases in a rat model. WAG/Rij rats were randomized into three groups and underwent ECT with i.v., i.t., or i.v. + i.t. injection of BLM. Tumor volumes and oxygenation were measured by means of ultrasound and photoacoustic imaging. Moreover, liver and tumor tissue were analyzed by histology and immunohistochemistry. The i.v. and i.v. + i.t. groups exhibited a 44.0% and 46.6% reduction in oxygen saturation of the tumor tissue when compared to pretreatment values, whereas the i.t. group only showed a reduction of 35.2%. The extent of tumor tissue necrosis did not statistically differ between the groups. However, the i.t. group showed a tendency towards a lower necrosis rate. Cell proliferation, apoptotic cell death, vascularization, and immune cell infiltration were comparable in the treated tumors of the three groups. ECT with i.v. administration of BLM should be preferred in clinical practice, as the combined i.v. + i.t. therapy did not show superior oncological outcomes in the present study.

Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches.

Pulmonary toxicity is a serious side effect of some specific anticancer drugs. Bleomycin is a well-known anticancer drug that triggers severe reactions in the lungs. It is an approved drug that may be prescribed for the treatment of testicular cancers, Hodgkin's and non-Hodgkin's lymphomas, ovarian cancer, head and neck cancers, and cervical cancer. A large number of experimental studies and clinical findings show that bleomycin can concentrate in lung tissue, leading to massive oxidative stress, alveolar epithelial cell death, the proliferation of fibroblasts, and finally the infiltration of immune cells. Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis. Both fibrosis and pneumonitis are serious concerns for patients who receive bleomycin and may lead to death. Therefore, the management of lung toxicity following cancer therapy with bleomycin is a critical issue. This review explains the cellular and molecular mechanisms of pulmonary injury following treatment with bleomycin. Furthermore, we review therapeutic targets and possible promising strategies for ameliorating bleomycin-induced lung injury.

RNA-sequencing reveals differential fibroblast responses to bleomycin and pneumonectomy.

Pulmonary fibrosis is characterized by pathological accumulation of scar tissue in the lung parenchyma. Many of the processes that are implicated in fibrosis, including increased extracellular matrix synthesis, also occur following pneumonectomy (PNX), but PNX instead results in regenerative compensatory growth of the lung. As fibroblasts are the major cell type responsible for extracellular matrix production, we hypothesized that comparing fibroblast responses to PNX and bleomycin (BLM) would unveil key differences in the role they play during regenerative versus fibrotic lung responses. RNA-sequencing was performed on flow-sorted fibroblasts freshly isolated from mouse lungs 14 days after BLM, PNX, or sham controls. RNA-sequencing analysis revealed highly similar biological processes to be involved in fibroblast responses to both BLM and PNX, including TGF-ß1 and TNF-α. Interestingly, we observed smaller changes in gene expression after PNX than BLM at Day 14, suggesting that the fibroblast response to PNX may be muted by expression of transcripts that moderate pro-fibrotic pathways. Itpkc, encoding inositol triphosphate kinase C, was a gene uniquely up-regulated by PNX and not BLM. ITPKC overexpression in lung fibroblasts antagonized the pro-fibrotic effect of TGF-ß1. RNA-sequencing analysis has identified considerable overlap in transcriptional changes between fibroblasts following PNX and those overexpressing ITPKC.