Methotrexate-induced Lung Research Articles

The effects of cannabidiol against Methotrexate-induced lung damage.

Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs. Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1ml of 5mg/kg CBD for 7days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant. Remarkably, CBD treatment reversed these findings. This study highlights CBD's potential in mitigating MTX-induced lung damage, suggesting its therapeutic promise.

High-intensity intermittent training ameliorates methotrexate-induced acute lung injury

Inflammation and oxidative stress are recognized as two primary causes of lung damage induced by methotrexate, a drug used in the treatment of cancer and immunological diseases. This drug triggers the generation of oxidants, leading to lung injury. Given the antioxidant and anti-inflammatory effects of high-intensity intermittent training (HIIT), our aim was to evaluate the therapeutic potential of HIIT in mitigating methotrexate-induced lung damage in rats. Seventy male Wistar rats were randomly divided into five groups: CTL (Control), HIIT (High-intensity intermittent training), ALI (Acute Lung Injury), HIIT+ALI (pretreated with HIIT), and ALI + HIIT (treated with HIIT).HIIT sessions were conducted for 8 weeks. At the end of the study, assessments were made on malondialdehyde, total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (Gpx), myeloperoxidase (MPO), interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-α), gene expression of T-bet, GATA3, FOXP3, lung wet/dry weight ratio, pulmonary capillary permeability, apoptosis (Caspase-3), and histopathological indices.Methotrexate administration resulted in increased levels of TNF-α, MPO, GATA3, caspase-3, and pulmonary edema indices, while reducing the levels of TAC, SOD, Gpx, IL-10, T-bet, and FOXP3. Pretreatment and treatment with HIIT reduced the levels of oxidant and inflammatory factors, pulmonary edema, and other histopathological indicators. Concurrently, HIIT increased the levels of antioxidant and anti-inflammatory factors.

Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone

PurposeLung fibrosis is a heterogeneous lung condition characterized by excessive accumulation of scarred tissue, leading to lung architecture destruction and restricted ventilation. The current work was conducted to examine the probable shielding influence of cinnamic acid against lung fibrosis induced by methotrexate.MethodsRats were pre-treated with oral administration of cinnamic acid (50 mg/kg/day) for 14 days, whereas methotrexate (14 mg/kg) was orally given on the 5th and 12th days of the experiment. Pirfenidone (50 mg/kg/day) was used as a standard drug. At the end of the experiment, oxidative parameters (malondialdehyde, myeloperoxidase, nitric oxide, and total glutathione) and inflammatory mediators (tumor necrosis factor-α and interleukin-8), as well as transforming growth factor-β and collagen content, as fibrosis indicators, were measured in lung tissue.ResultsOur results revealed that cinnamic acid, as pirfenidone, effectively prevented the methotrexate-induced overt histopathological damage. This was associated with parallel improvements in oxidative, inflammatory, and fibrotic parameters measured. The outcomes of cinnamic acid administration were more or less the same as those of pirfenidone. In conclusion, pre-treatment with cinnamic acid protects against methotrexate-induced fibrosis, making it a promising prophylactic adjuvant therapy to methotrexate and protecting against its possible induction of lung fibrosis.

Evaluation of the Protective Effect of Citral, Silymarin, and Thymoquinone on Methotrexate-Induced Lung Injury in Rats.

Several studies have reported that methotrexate is an anti-cancer and immunosuppressive drug leading to lung injury. Therefore, the present study aimed to investigate the protective effects of silymarin, citral, and thymoquinone on methotrexate-induced pulmonary toxicity. Forty-eight rats were divided into six groups, including healthy, Methotrexate, and drug carrier control groups and silymarin, citral, and thymoquinone treatment groups. At the end of the experiment, the studied rats were anesthetized and sacrificed by CO2. Lung tissue samples were isolated to measure the antioxidant activity and histopathological evaluation. In the thymoquinone treatment group, the concentration of total antioxidant capacity and Malondialdehyde increased and decreased significantly, respectively, compared to the methotrexate group. The histopathological evaluation of the lung of the methotrexate group showed hemorrhage and congestion, the nodule-like accumulation of mononuclear inflammatory lymphocytes around the blood vessel, a small number of neutrophils around the blood vessel, and the inflammatory cells around the small vessels. However, no significant pathological alterations were observed in the treatment groups, especially the thymoquinone treatment group. Thymoquinone has the greatest protective effect on methotrexate-induced lung injury, probably due to its antioxidant effect.

Prevalence of Methotrexate-Induced Lung Involvement in Psoriasis Patients

Background: Seventy five psoriasis patients who visited the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 were examined to assess the incidence of methotrexate-induced lung involvement. Long-term methotrexate therapy often results in lung involvement, which may present as pleuritis, pneumonia, fibrosis, and obliterative bronchiolitis. Clinical evaluations and case data were retrospectively reviewed. Out of the Seventy five individuals tested, the results indicate that 15 (15%) had mild to moderate lung involvement, while 4 (4%) had severe lung involvement. In 67% of the patients, there was no discernible lung involvement. The frequency of methotrexate-induced lung involvement at the Pakistani Institute of Medical Sciences is quite low, despite the fact that it is a possible side effect of long- term methotrexate usage for psoriasis patients. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Objectives: Identifying the frequency of methotrexate-induced lung involvement in psoriasis patients seen at the Pakistani Institute of Medical Sciences in Islamabad from January 2021 to January 2022 is the goal of this research. Methods: Seventy five psoriasis patients who were seen between January 2021 and January 2022 at the Pakistani Institute of Medical Sciences (PIMS) in Islamabad were the subject of the research. Lung involvement was evaluated by a retrospective examination of the case files and clinical evaluation, which may have required pulmonary function tests, chest X-rays, or even chest CT scans. There was no discernible lung involvement, mild to moderate lung involvement, severe lung involvement, or no lung involvement at all. Results: Seventy-five individuals were examined; fifteen (15%) had mild to moderate lung involvement, four (4%) had severe lung involvement, and sixty-seven (67%) had no discernible lung involvement. Conclusion: According to the study's findings, although methotrexate-induced lung involvement is a possible side effect of long-term methotrexate usage for people with psoriasis, it is not very common at the Pakistani Institute of Medical Sciences. 67% of the individuals in the study had no observable lung involvement. If long-term methotrexate usage raises the likelihood of lung involvement in psoriasis patients, further investigation is required. Keyword: Methotrexate, Psoriasis, Lung Involvement, Prevalence, PIMS

The potential role of pumpkin seeds oil on methotrexate-induced lung toxicity

Many chemotherapeutic drugs cause adverse pulmonary reactions leading to severe pulmonary disease. Though methotrexate (MTX) is used for the treatment of cancer and other diseases, it is highly toxic with multiple adverse effects including pulmonary toxicity. Essential oils represent an open frontier for pharmaceutical sciences due to their wide range of pharmacological properties. Pumpkin seeds oil (PSO) was used to investigate its ability to alleviate methotrexate-induced lung toxicity in rats. Lung tissue from MTX-treated group revealed a decrease in malondialdehyde, glutathione, and nitric oxide accompanied by a marked inhibition in cholinesterase activity, and enhanced catalase activity, tumor necrosis factor-α, interleukin-6 and vascular endothelial growth factor levels. Analysis of PSO revealed that the oil was rich in hexadecanoic acid, decane methyl esters, squalene, polydecane, docosane, and other derivatives. Administration of PSO ameliorated the oxidant/antioxidant and proinflammatory changes induced by MTX in the lung tissue. Histological examinations confirmed the potency of PSO in reducing the histopathological alterations induced by MTX. Immunohistochemical analysis showed decreased nuclear factor-kappa B and caspase 3 expression after PSO. The present data indicated the protective efficiency of PSO against MTX-induced lung injury by decreasing oxidative damage, inflammation and apoptosis and could thus be recommended as an adjuvant therapy.

Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity.

Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1β, and TGF-β1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.

Methotrexate-induced lung injury in a patient of psoriasis

Methotrexate is a widely used medication with an array of recognized side effects and it is often the first-line drug prescribed for connective tissue disorders and rheumatological diseases. The aim of the study was to present a case demonstrating methotrexate-induced lung injury in a patient of psoriasis.

Inhibitory effect of whey protein concentrate on SARS-CoV-2-targeted furin activity and spike protein-ACE2 binding in methotrexate-induced lung damage.

This study aims to investigate the effects of whey proteins on SARS CoV-2 in methotrexate-induced lung tissue damage in rats. To determine the possible effects, rats were divided into four groups as control, control + whey, methotrexate (20mg/kg, i.p.) and methotrexate + whey. Whey protein concentrate (2g/kg, oral gavage) was administered for 10days. Cytokine levels were measured and protein electrophoresis was carried out in serum samples. Lipid peroxidation, nitric oxide and glutathione level, and superoxide dismutase and glutathione S transferase activities were determined in lung samples. Inhibition of SARS CoV-2-targeted lung furin activity and SARS CoV-2 spike protein-angiotensin converting enzyme binding with whey protein concentrate were also measured in each group. In conclusion, whey protein concentrate improved methotrexate-induced lung damage and inhibited lung furin activity targeting SARS-CoV-2 S1/S2 site cleavage and SARS CoV-2 spike protein-angiotensin converting enzyme binding. Whey proteins are potential protective candidates that inhibit SARS CoV-2-related interactions, even in methotrexate-induced lung injury. PRACTICAL APPLICATIONS: Whey proteins have anticarcinogenic, antihypertensive, antioxidant, antibacterial, antiviral, and immunomodulating properties due to the protein, bioactive peptide, and essential amino acid content. Methotrexate is a folate antagonist and inhibits cell proliferation and purine synthesis. The combined use of whey protein concentrate and methotrexate may be an alternative in the development of new strategies to the treatment approaches against COVID-19. In addition, according to the results of this study, it is thought that the protective effect of whey proteins in healthy conditions before encountering the SARS CoV-2 may be higher than those who have never used it.

New insights into the treatment of CTD-ILD.

Interstitial lung disease (ILD) can arise in a variety of connective tissue diseases (CTDs) and various treatment interventions are being explored. In 2020, advances in the treatment of CTD-associated ILD have included the re-evaluation of methotrexate-induced lung injury and emerging insights on anti-IL-6 therapy and anti-fibrotic therapy in this condition.

Unilateral Methotrexate-Induced Lung Injury with Foreign Bodies in the Airway: A Case Report

Unilateral Methotrexate-Induced Lung Injury with Foreign Bodies in the Airway: A Case Report

Methotrexate Induced Lung Toxicity-A Case Report

Methotrexate (MTX) belongs to a class of antimetabolites. It may cause serious side effects like lung problems, lung infections. Methotrexate-induced lung disease, as well as acute or chronic interstitial pneumonitis, is a potentially risky sore, which can happen intensely whenever, amid treatment and has been accounted for at low doses. The diagnosis of drug-induced pulmonary toxicity is generally settled in light of clinical discoveries. The present report describes a case of methotrexate-induced lung toxicity. Biopsy that had done reported as relapsed lymphoma. Then he got admitted for high dose methotrexate and rituximab followed by folinic acid rescue. He tolerated 2 chemotherapies well, without any major complications. He developed fever, cough with expectoration and breathlessness. In view of persisting high grade fever, associated with cough and breathing difficulty, pulmonology consultation was sought and CT done. In medication-induced lung toxicity, the radiologic patterns seen are exceeding factor and rely upon the kind of unfavorable response the patient is experiencing. One possibility in the clinical setting is methotrexate induced lung changes. Differential diagnosis (DD) is alveolitis due to infection. In view of suspected methotrexate induced lung toxicity, planned to withhold next dose of Methotrexate. He was started on high dose steroids. The patient symptomatically improved, fever subsided, counts improved. Prompt diagnosis is vital in light of the fact that early medication actuated lung harm will regularly relapse with cessation of treatment. It was found that the severity of the methotrexate induced lung toxicity is a probable adverse drug reaction (ADR) with Naranjo score of 7.

Carvacrol and pomegranate extract in treating methotrexate-induced lung oxidative injury in rats.

BackgroundThis study was designed to evaluate the effects of carvacrol (CRV) and pomegranate extract (PE) on methotrexate (MTX)-induced lung injury in rats.Material/MethodsA total of 32 male rats were subdivided into 4 groups: control (group I), MTX treated (group II), MTX+CRV treated (group III), and MTX+PE treated (group IV). A single dose of 73 mg/kg CRV was administered intraperitoneally to rats in group III on Day 1 of the investigation. To group IV, a dose of 225 mg/kg of PE was administered via orogastric gavage once daily over 7 days. A single dose of 20 mg/kg of MTX was given intraperitoneally to groups II, III, and IV on Day 2. The total duration of experiment was 8 days. Malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC), and oxidative stress index (OSI) were measured from rat lung tissues and cardiac blood samples.ResultsSerum and lung specimen analyses demonstrated that MDA, TOS, and OSI levels were significantly greater in group II relative to controls. Conversely, the TAC level was significantly reduced in group II when compared to the control group. Pre-administering either CRV or PE was associated with decreased MDA, TOS, and OSI levels and increased TAC levels compared to rats treated with MTX alone. Histopathological examination revealed that lung injury was less severe in group III and IV relative to group II.ConclusionsMTX treatment results in rat lung oxidative damage that is partially counteracted by pretreatment with either CRV or PE.

Protective effects of erythropoietin and N-acetylcysteine on methotrexate-induced lung injury in rats.

Methotrexate (MTX) is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO) and N-acetyl-cysteine (NAC) on MTX-induced lung injury in rats. Animal experiment. Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and inflammation and congestion scores in lung tissues were evaluated. In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p<0.005). In EPO group MDA, CAT, and SOD were higher, but not significant than those in group NAC (p>0.005). In group MTX both scores were significantly higher than in sham (p<0.005). The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005). EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.

62-Year-Old Woman With Fever, Dyspnea, Pleuritic Chest Pain, and Weight Loss

A 62-year-old woman with rheumatoid arthritis (RA) presented for evaluation of chronic pleuritic chest pain, dyspnea, cough, odynophagia, fatigue, weight loss of 16.6 kg (30 lb), and migratory joint pains. Ten years earlier, RA had been diagnosed on the basis of polyarticular inflammatory arthritis. Rheumatoid factor (RF) had subsequently been positive and anticyclic citrullinated peptide (anti-CCP) antibodies negative. No signs or symptoms of underlying connective tissue disease (CTD) had been reported, and no serologic testing for CTD performed. For the past 6 years, the patient had been taking etanercept, methotrexate, and prednisone. Five months before presentation, findings on computed tomography (CT) of the chest reportedly were consistent with RA-associated interstitial lung disease (RA-ILD) or methotrexate-induced lung injury. Pulmonary function testing displayed a restrictive pattern. Methotrexate use was discontinued. One month before presentation, use of etanercept was discontinued because of leukopenia and perioral “fever blisters,” presumed to be adverse effects of medication. On arrival to our institution, her medication regimen was prednisone at 7.5 mg/d, sitagliptin-metformin, levothyroxine, lisinopril, pantoprazole, and simvastatin, as well as nonsteroidal anti-inflammatory drugs as needed.

Methotrexate-induced pneumonitis in a patient with Crohn's disease

Pulmonary toxicity is a well recognised but infrequent adverse event of treatment with methotrexate. The vast majority of cases have occurred in patients with rheumatoid arthritis; here we present the case of a 44-year old woman with ileo-colonic Crohn's disease who developed methotrexate pneumonitis. The patient had a 10 year history of Crohn's disease and, in the last 18 months, she was treated with oral methotrexate because of steroid-dependency and intolerance to thiopurines. She was admitted to the hospital because of acute dyspnoea, non-productive cough and fever. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity, and pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity. Blood cultures for pathogenic bacteria or fungi were negative as well as serologic tests against major pneumotropic agents. Methotrexate-induced lung injury was considered: the drug was discontinued and the patient received a steroid course with rapid symptomatic improvement. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal. To our knowledge this is the second reported case of methotrexate-induced pneumonitis occurring in a patient with Crohn's disease. A definite diagnosis has been made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings.

Accelerated Pulmonary Nodulosis and Sterile Pleural Effusion in a Patient With Psoriatic Arthropathy During Methotrexate Therapy

Pulmonary nodulosis and sterile pleural exudates are well-known extra-articular manifestations in rheumatoid arthritis patients with a positive rheumatoid factor. In some patients, treatment with methotrexate has been postulated as the trigger of these complications. We report a patient with psoriatic arthropathy, negative RF, negative anticyclic citrulinated peptide antibodies but positive antibodies to cardiolipin who developed massive sterile pleural empyema and multiple cavitary pulmonary nodules during methotrexate treatment. We suggest that awareness of methotrexate-induced lung and pleural complications should be extended to other than rheumatoid arthritis diseases, not necessarily accompanied by rheumatoid factor or anticyclic citrulinated peptide antibodies.

Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group.

Toxicity limits the use of methotrexate. To identify risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. Case-control study. One private and five academic rheumatology practices. Methotrexate recipients with rheumatoid arthritis with and without lung injury. Potential risk factors examined were sociodemographic and lifestyle characteristics, medical history, clinical and ancillary features and treatment of rheumatoid arthritis before methotrexate therapy, and characteristics of methotrexate therapy. Cases of lung injury were defined according to the modified criteria of Searles and McKendry. Ninety-four percent of the study participants were white, and 67% were women. Case-patients (n = 29) were older than controls (n = 82) (61.5 compared with 54.5 years of age). The strongest predictors of lung injury, after adjustment for other variables, were older age (odds ratio [OR], 5.1 [95% CI, 1.2 to 21.1]), diabetes (OR, 35.6 [CI, 1.3 to infinity]), rheumatoid pleuropulmonary involvement (OR, 7.1 [CI, 1.1 to 45.4]), previous use of disease-modifying antirheumatic drugs (OR, 5.6 [CI, 1.2 to 27.0]), and hypoalbuminemia (OR, 19.5 [CI, 3.5 to 109.7]). Previous use of disease-modifying antirheumatic drugs and hypoalbuminemia had very large attributable risks. Knowledge of the risk factors that predispose patients with rheumatoid arthritis to the toxic effects of methotrexate on the lung may provide a rationale for monitoring high-risk patients and may facilitate their management.

Methotrexate-induced lung injury: risk factors identified

Methotrexate-induced lung injury: risk factors identified

Phase II Trial of 10-Edam in Patients with Advanced Colorectal Carcinoma

10-Edam (10-ethyl-10-deaza-aminopterin), an antifolate derivative, was administered to 14 chemotherapy-naive patients with advanced colorectal carcinoma. The drug was given weekly by intravenous route at an initial dose of 80 mg/m2, with escalation or attenuation according to tolerance. Mucositis was dose limiting and occurred in 11 of 14 patients (78.6%). Removal from the study was required in one patient due to progressive pulmonary fibrosis that was histologically identical to methotrexate-induced lung damage. Toxicity was otherwise mild to moderate and included diarrhea, constipation, abdominal discomfort, anorexia, nausea/vomiting, rash, and fatigue. There were no responses to 10-Edam in this study, 95% confidence interval (0-0.23). Stable disease was achieved in four patients; the remaining 10 patients demonstrated progression within 9 weeks of initiating systemic therapy. 10-Edam employed at this dosage and schedule was not effective as a treatment against advanced colorectal carcinoma.