Mechanisms Of Pulmonary Toxicity Research Articles

A study of inflammatory biomarkers in crystalline silica exposed rock drillers

BackgroundCrystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated.AimsTo assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS.MethodsRock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study.ResultsThe rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents.ConclusionExposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

Mechanisms of Pulmonary Toxicity of Perfluoro-n-Alkane Pyrolysis Products with Consideration of the Structural Features of the Blood-Air Barriers.

Perfluoroisobutylene a is pulmonotoxic chemical generated during pyrolysis of perfluoro-nalkanes (polytetrafluoroethylene). The mechanisms of acute pulmonary toxicity induced by perfluoroisobutylene have not been studied yet. The analysis of tissues of brown frogs showed that the products of polytetrafluoroethylene pyrolysis induce typical inflammatory response in the lungs (fluid accumulation, erythrocyte stasis, desquamation of the epithelium, and capillary plethora in lung septa) and oropharyngeal cavity (degeneration of ciliated epithelium, hyperemia of underlying vessels with plasmatic imbibition of the connective tissue, and margination of segmented leukocytes and monocytes). The absence of surfactant is a specific feature of the blood-air barrier of the oropharyngeal cavity in frogs compared to the lungs. It can be hypothesized that toxic effects of perfluoroisobutylene are determined by its influence on epithelial (pneumocytes and cells of nonkeratinized stratified ciliated epithelium) and endothelial cells. Even though the effects of the agent on surfactant cannot be excluded, they do not determine the probability of development of inflammatory response.

Acute Eosinophilic Pneumonia Complicated by Daptomycin

SESSION TITLE: Student/Resident Case Report Poster - Critical Care V SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Acute Eosinophilic Pneumonia (AEP) is a rare and potentially fatal respiratory syndrome. The most common cause is idiopathic, but it also is associated with drugs and toxins, infections and radiation therapy.1 We describe a probable case of AEP complicated by daptomycin therapy. CASE PRESENTATION: A 55-year-old male, former smoker, presented to the hospital with left olecranon bursitis complicated by MRSA. He underwent debridement and was placed on i.v. daptomycin and discharged home. On day 7, the patient developed progressive shortness of breath, low grade fevers, and a dry cough. 2 days later, he presented with T=97.6, BP 150/80, HR 112, RR 22, and oxygen saturation 82% on room air consistent with acute hypoxic respiratory failure. He was placed on high flow oxygen and CTA chest demonstrated bilateral, diffuse, patchy ground glass infiltrates with mild bibasilar bronchiectasis and upper lobe paraseptal emphysema. White blood cell count was 17.5 with 4.4% eosinophils (0-5.0%). Daptomycin induced pulmonary toxicity was immediately suspected and was subsequently discontinued. He was transitioned to i.v. vancomycin and cefepime and initiated on high dose i.v. corticosteroids. Bronchoscopy was performed the next day without eosinophilia but with cytology disclosing foamy histiocytes and mixed inflammation. Subsequent cultures disclosed no evidence of microorganisms. He made significant improvement with resolution of peripheral eosinophilia. He was discharged on an 8 week steroid taper with follow up CT chest revealing almost complete resolution of airspace disease. DISCUSSION: AEP is a rare and potentially serious complication of daptomycin theray. Its mechanism of pulmonary toxicity is possibly associated with irreversibly binding to surfactant.2 A clinical diagnosis of AEP can be made in patients who meet the following criteria: A febrile illness of less than one week, hypoxemic respiratory failure, diffuse pulmonary opacities on chest radiograph, BAL differential cell count showing eosinophilia, and absence of known causes of eosinophilic pneumonia asthma or atopic disease.1 Treatment involves early discontinuation of offending agent and prompt initiation of corticosteroids. CONCLUSIONS: Early recognition was critical and led to the quick recovery of this form of daptomyocin induced hypoxic respiratory failure. In our case, although there was no evidence of eosinophilia, it did meet the Naranjo definitive criteria for adverse drug reaction.3 Reference #1: Cordier J, Cottin V. Eosinophilic pneumonias. In: Interstitial Lung Disease, 5th, Schwarz MI, King TE Jr. (Eds), People's Medical Publishing House-USA, Shelton, CT 2011. P.833. Reference #2: Mehta P, Wong W, Ramalingam S, Aucoin P, Chandak T Daptomycin-induced acute eosinophilic pneumonia an emerging clinical entity. Chest. 2012;142: 1042A-1042A. Reference #3: Naranjo CA, Busto U, Sellers EM, et al. (1981). A method for estimating the probability of adverse drug reactions. Clinical Pharmacology and Therapeutics. 30 (2): 239-45. DISCLOSURE: The following authors have nothing to disclose: Kurt Olson, Arooj Kayani, Rajeev Saggar No Product/Research Disclosure Information

Mechanisms of pulmonary toxicity developed at low and high doses of dextran-coated magnetite nanoparticles

Mechanisms of pulmonary toxicity developed at low and high doses of dextran-coated magnetite nanoparticles

Pneumopathies interstitielles diffuses médicamenteuses au cours des maladies systémiques

Immunosuppressants and immunomodulators are designed to regulate excessive immune response responsible for inflammatory lesions and are prescribed more and more in internal medicine. These drugs are known for their efficiency but with a significant toxicity including interstitial lung disease (ILD). Some factors liable to pulmonary toxicity include advanced age, genetic polymorphism and the existence of prior pulmonary disease. Cytotoxicity and hypersensitivity are the main mechanisms of pulmonary toxicity. There is no universal classification of drug induced-lung disease. Theoretically, drugs may be responsible for all histological aspects of ILD. Methotrexate is the most well-known drug as a provider of ILD with a prevalence of 0.3 to 11.6%. Some cases of ILD have also been reported with the new biologics used in systemic diseases. The diagnostic approach to the suspicion of drug ILD is to eliminate non-medicinal causes of pneumonia including infections and tumors before exploring the clinical symptomatology and the results of imaging and bronchoalveolar lavage cell profile. The analysis of the clinical symptomatology check the compatibility of the chronology of clinical and/or radiological pneumonia with the medication suspected. Subsequently, data from the clinical case are compared with those of the literature. Treatment involves stopping the suspected drug. The use of corticosteroids may be required in case of signs of severity or a lingering evolution.

Sirolimus-induced pneumonitis

A 15 year-old girl with reflux nephropathy ESKD underwent a related renal transplant in March 2000. Initial immunoupprressants administered to the patient included cyclosporine, azathioprine, and prednisolone. In January 2003, she had acute allograft dysfunction due to CNI toxicity with chronic allograft nephropathy (CAN) detected by biopsy. Thus, cyclosporine and azathioprine were withdrawn and replaced with rapamycin and mycophenolate mofetil. The serum creatinine level at the time of the change was 2.2 mg/dL, urine routine microscopy showed Trace proteinuria. Sirolimus levels were monitored and kept between 5 and 10 ng/mL. With the withdrawal of cyclosporine, renal parameters showed significant improvement and the serum creatinine level stabilized at 1.6 mg/dL. In April 2007, after approximately four years of the change, the patient presented with progressive breathlessness without any other systemic manifestations or expectoration. Computerised tomographic (CT) of the chest showed bilateral, mosaic ground-glass opacification and thickened interlobular septae [Figure 1]. Bronchoscopy, broncheoalveolar lavage, and pulmonary biopsy excluded infective etiology such as pneumocystis carnii, pulmonary Koch's, and fungal pneumonia [Figure 2]. By exclusion, the etiology was narrowed down to rapamycin-induced parenchymal lung lesions. Thus, rapamycin was withdrawn and the patient was serially followed on two drugs, mycophenolate mofetil and prednesolone. She improved clinically in twelve weeks and radiologically over six months. The followup CT of the chest showed significant clearing of the reticular and ground glass opacities [Figure 3]. Figure 1 Sirolimus-induced pneumonitis Figure 2 Lung biopsy showing parenchymal lung lesion. Transbronchial lung biopsy shows normal bronchial epithelium, bronchial cartilage, and surrounding lung tissue. Alveoli contain a granular proteinaceous material (arrows). This material is also seen lying loosely ... Figure 3 Resolved Sirolimus-induced pneumonitis Sirolimus (rapamycin) is an immunosuppressive agent that was approved by the Food and Drug Administration (FDA) in 1999 for use in renal transplantation. The macrocyclic triene antibiotic is produced by the actinomycete, Streptomyces hygroscopicus. Sirolimus acts by arresting the progression of cells from the G1 phase to the S phase by interaction with at least two intracellular proteins. Forty-three cases of pulmonary toxicity due to Sirolimus (rapamycin) have been reported including cases of interstitial pneumonitis, fibrosing alveolitis, and pulmonary hemorrhages.[1] The majority of these cases have occurred in renal transplant recipients within the initial six months of iniciation of the drug and lesions have generally responded to the lowering or withdrawal of the drug dosage. Most of the patients present with progressive breathlessness, weakness, cough, and bilateral lower zone pulmonary opacities, and over half of the cases present with fever. Our patient fulfilled all these criteria, except for the delayed presentation. The mechanism of pulmonary toxicity of Sirolimus (rapamycin) is not clear; direct toxicity, immunomediated toxicity, or both have been proposed as the mechanism.[1] The presence of lymphocytes in lung biopsies suggests an immunomediated mechanism. Possibly, some cryptic pulmonary antigens induce an autoimmune response. However, the rapid clearance of lung lesions with the discontinuation of the drugor dose reduction without steroids, favors direct toxicity.

Pulmonary and Hepatic Toxicity Due to Nitrofurantoin

Aim: To present a case of combined pulmonary and hepatic toxicity due to nitrofurantoin.Clinical features: A 79‐year‐old female developed painless jaundice and exertional dyspnoea over an 8‐week period. A chest X‐ray and computerised tomography chest scan revealed interstitial lung disease with respiratory function tests showing a markedly reduced diffusing lung capacity for carbon monoxide (6.72 mL/min/mmHg). Liver function tests were markedly elevated, consistent with acute hepatitis, but returned to normal following cessation of the drug.Discussion: Combined hepatic and pulmonary toxicity due to nitrofurantoin is rare.1‐3 The mechanism for pulmonary toxicity is thought to be secondary to the generation of oxygen free radicals in combination with immune‐mediated injury. An immune mechanism is similarly thought to cause the hepatic toxicity.1

Phase I and pharmacokinetic study of KW-2149 given by 24 hours continuous infusion

KW-2149 is a new mitomycin C (MMC) analog, forming DNA-DNA and DNA-protein crosslinking 20-fold more effectively than MMC. Because of its equal or superior in vitro and in vivo activity compared to MMC, a phase I study was initiated with an intravenous bolus injection every three weeks. This study was interrupted after dose escalation from 5 mg/m2 to 100 mg/m2 because of subacute and dose dependent pulmonary toxicity. Because of the lack of other end-organ toxicity, the moderate hematological toxicity and the observed antitumor effect, a second phase I study was initiated with a 24 hour continuous infusion. The starting dose was 50 mg/m2 and further escalation depended on observed pulmonary toxicity. Four patients were entered into this study and the received in total 17 courses. Toxicity was again mainly restricted to the lungs with one patient suffering grade 2 dyspnoe and another one grade 1 dyspnoe. Three patients had a substantial change in the carbon monoxide (CO) diffusion capacity. Pharmacokinetic data from these patients showed very low plasma levels both for KW-2149, as for both known metabolites M-16 and M-18. This study demonstrates that pulmonary toxicity continues to occur with KW-2149, in spite of the assurance of low plasma levels of both the parent compound and the known metabolites. The interesting activity of this compound has stimulated further in-depth research towards mechanisms of pulmonary toxicity and means of preventing them.