Can angiotensin-converting enzyme inhibitors protect against symptomatic radiation pneumonitis?

This study was designed to determine whether patients taking angiotensin-converting enzyme (ACE) inhibitors while receiving radiation therapy for lung cancer are protected from developing symptomatic radiation pneumonitis. The records of 213 eligible patients receiving thoracic irradiation for lung cancer with curative intent at Duke University Medical Center from 1994-1997 were reviewed. Of the 213 patients, 26 (12.2%) were on ACE inhibitors (usually for the management of hypertension) during radiotherapy (group 1); the remaining 187 patients (group 2) were not. Patients were irradiated, with fields shaped to protect normal tissues, with total doses of 50-80 Gy. After treatment, patients were generally followed every 3 months for 2 years, then every 6 months thereafter. Symptomatic radiation pneumonitis was scored according to modified National Cancer Institute Common Toxicity Criteria (i.e., radiographic changes alone were not sufficient for the diagnosis of pneumonitis). There was no difference in the incidence of pneumonitis between the two groups (P = 0.75). Fifteen percent of the patients on ACE inhibitors (group 1) developed symptomatic radiation-induced lung injury compared to 12% of the patients not receiving these drugs (group 2). Although patients in group 1 tended to develop pneumonitis slightly sooner than did patients in group 2, this difference also was not significant (P = 0. 8). Within the dose range prescribed for treating hypertension, ACE inhibitors do not appear to either decrease the incidence or delay the onset of symptomatic radiation pneumonitis among lung cancer patients receiving thoracic irradiation.     

Increased levels of free circulating DNA in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is difficult to diagnose because of numerous interstitial lung diseases with similar symptoms. As serum DNA has proven useful for early lung cancer detection, we aimed to define the relevance of this marker in discriminating IPF from other fibrotic and nonfibrotic/nonmalignant lung diseases. DNA was quantified in 191 subjects: 64 healthy individuals, 58 patients with IPF, 17 patients with nonspecific pulmonary fibrosis (13 idiopathic nonspecific interstitial pneumonia, 4 chronic hypersensitivity pneumonitis), and 52 patients with other diffuse/nonmalignant lung diseases. The median value of free DNA in IPF patients was 61.1 ng/mL (range 7.1-405), which was significantly higher than that of healthy donors (median 6.8, range 2.2-184) (p<0.001) and that of patients with other diffuse/nonmalignant lung diseases (median 28.0, range 4.2-281) (p=0.004). The area under the ROC curve was 0.926 (95% CI 0.879-0.973) when IPF patients were compared with healthy donors, and 0.702 (95% CI 0.609-0.796) when a comparison was made with non-IPF pulmonary diseases. In conclusion, we observed significantly higher levels of free circulating DNA in patients with IPF than in those with other fibrotic or diffuse/nonmalignant lung diseases.     

非小细胞肺癌患者血清淀粉样蛋白A水平与放射性肺炎的相关性研究

目的:评估非小细胞肺癌患者血清淀粉样蛋白A(SAA)水平与发生放射性肺炎(RP)的相关性。方法:选取我院确诊为非小细胞肺进行肺部病灶放射治疗的患者118例,评价是否发生放射性肺炎,并在放疗前及放疗剂量达到43 GY时分别抽取患者血清样本,应用酶联免疫法(ELISA)检测患者血清淀粉样蛋白A含量。结果:43例患者发生了放射性肺炎,发生放射性肺炎组患者的放疗前血清淀粉样蛋白A水平明显高于未发生放射性肺炎组,两组对比,差异有统计学意义(P0.05)。而在放疗剂量达到43Gy时,发生放射性肺炎组患者的血清淀粉样蛋白A水平与未发生放射性肺炎组患者相比,差别无统计学意义。结论:对于非小细胞肺癌患者,通过检测放疗前血清淀粉样蛋白A水平可以预测放射性肺炎的发生。     

Pulmonary Complications of Drug Abuse

Complications resulting from drug abuse more frequently affect the lung than any other organ. The spectrum of pulmonary complications associated with drug abuse is wide. The current practice of using mixtures of drugs is mainly responsible for the increase in pulmonary complications. The chief complications observed in a series of 241 drug abuse patients were aspiration pneumonitis (12.9 percent), pulmonary edema (10.0 percent), and pneumonia (7.5 percent).     

Unilateral radiation pneumonitis in sheep: physiological changes and bronchoalveolar lavage

Radiation pneumonitis is a life-threatening result of therapeutic thoracic irradiation, yet its mechanisms are poorly understood. We studied the effects of unilateral lung irradiation (3,000 rad) in sheep from the immediate response to the later development of radiation pneumonitis. We defined radiation pneumonitis by its diagnostic clinical feature, radiographic infiltration of the irradiated zone with a straight margin corresponding to the radiation port. The immediate response in the few hours after irradiation was characterized by cough, labored respiration, hypoxemia (arterial PO2 decreased 19 Torr), mild pulmonary hypertension (pulmonary arterial pressure increased 20%), and lymphopenia. Hemodynamics and gas exchange returned to normal by day 2 but became abnormal again before or during radiation pneumonitis at 32 +/- 2 days. Respiratory distress, hypoxemia, and pulmonary hypertension recurred during radiation pneumonitis. Bronchoalveolar lavage during radiation pneumonitis contained increased neutrophils (19 +/- 4%, control = 7%), increased protein (0.27 +/- 0.1 g/dl, control = 0.12 +/- 0.03), and severely impaired ability to lower surface tension. Alveolar macrophages from both lungs during unilateral radiation pneumonitis exhibited impaired generation of superoxide after phorbol myristate (only a 30% increase). Normal control alveolar macrophages increased superoxide production after stimulation greater than 400%. We conclude that unilateral lung irradiation in sheep causes a mild immediate response followed by radiation pneumonitis at 1 mo. Unilateral radiation pneumonitis in this model is associated with ipsilateral neutrophilic alveolitis, increased bronchoalveolar lavage protein, and impaired surfactant function, as well as bilateral functional abnormalities of alveolar macrophages.     

Vascular response to radiation injury in the rat lung.

Changes in relative left-to-right lung blood flow ratios were followed as an index of vascular radiation injury in left-hemithorax-irradiated Sprague-Dawley rats. Single doses of 11 to 21 Gy gamma radiation resulted in a dose-dependent decrease in relative blood flow to the irradiated lung from 3 to 5 weeks after exposure during the development of pneumonitis. Blood flow returned to near normal by 5 weeks after lower doses (11-13.5 Gy). After a single dose of 15 Gy the left-to-right blood flow ratio recovered to 75% of normal at 12 weeks and leveled off. Following 18 Gy irradiation a second period of reduced flow began 16 weeks after exposure. After 21 Gy irradiation flow to the irradiated side remained low for 1 year after exposure. Rats that received a single dose of 18 Gy to the left hemithorax were also treated with one or two of the following drugs: captopril, cyproheptadine, dexamethasone, diethylcarbamazine, penicillamine, or theophylline. Dexamethasone was most effective at preventing the decrease in blood flow to the irradiated lung when treatment was continued through the pneumonitis period and dose was not tapered until 8 weeks after radiation exposure. All other drugs and drug combinations were, for the most part, virtually ineffective after the pneumonitis period. There was a relatively poor correlation with earlier vascular permeability surface area product studies. This suggests that endothelial damage, as well as damage to other cell types, contributes to the development of post-irradiation fibrosis in the lung.     

High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis

Radiation pneumonitis is an unpredictable complication of radiotherapy for lung cancer and a condition which can cause significant morbidity. The ability to identify patients at a high risk of developing pneumonitis is critical, since it will enable the individualization of the treatment plan. Because the cytotoxic effect of radiation is propagated through reactive oxygen species (ROS) and ROS-driven oxidative stress, the role of antioxidant defense systems in radiation pneumonitis was investigated. Using the pneumonitis-sensitive C3H/HeN mice as a model, we demonstrated that the antioxidant response of the lung correlated well with that of red blood cells (RBC). We then proceeded to test whether differences of RBC antioxidant response would predict the pneumonitis development in patients. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) activities and glutathione in RBC were measured at baseline and then weekly for 6 weeks of treatment in 15 eligible patients receiving concurrent chemo-radiotherapy for unresectable stage III NSCLC. Striking differences were found in the antioxidant activities of RBC with respect to the pneumonitis development. Those who developed pneumonitis showed higher SOD and lower GPX activities at baseline compared to those who did not (3.7 vs 6.8 units/mg for median SOD, 16.5 vs 10.7 nmol/min/mg for median GPX). The functional imbalance of SOD and GPX was displayed consistently throughout the treatment period. The sensitivity and specificity of pneumonitis prediction were further increased when the GPX/SOD ratio was analyzed (pretreatment P = 0.0046). Our results provide a strong rationale to monitor SOD and GPX activities of RBC to identify patients who are at risk of developing pneumonitis, and to implement a strategy of increasing the GPX/SOD ratio in order to lower the risk.     

COVID-19: Pathogenesis,cytokine storm and therapeutic potential of interferons

The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).     

Altered fatty acid composition of lung surfactant phospholipids in interstitial lung disease

Deterioration of pulmonary surfactant function has been reported in interstitial lung disease; however, the molecular basis is presently unclear. We analyzed fatty acid (FA) profiles of several surfactant phospholipid classes isolated from large-surfactant aggregates of patients with idiopathic pulmonary fibrosis (IPF; n = 12), hypersensitivity pneumonitis (n = 5), and sarcoidosis (n = 12). Eight healthy individuals served as controls. The relative content of palmitic acid in phosphatidylcholine was significantly reduced in IPF (66.8 +/- 2.5%; means +/- SE; P < 0.01) but not in hypersensitivity pneumonitis (78.5 +/- 1.8%) and sarcoidosis (78.2 +/- 3.1%; control 80.1 +/- 0.7%). In addition, the phosphatidylglycerol FA profile was significantly altered in the IPF patients, with a lower relative content of its major FA, oleic acid, at the expense of saturated FA. In the phosphatidylcholine class, a significant correlation between the impairment of biophysical surfactant function and decreased percentages of palmitic acid was noted. We conclude that significant alterations in the FA profile of pulmonary surfactant phospholipids occur predominantly in IPF and may contribute to the disturbances of alveolar surface activity in this disease.     

Speckle interferometry applied to pharmacodynamic studies: evaluation of parasite motility

The work reported here describes the application of the optical technique known as dynamic speckle interferometry to evaluate the motility of nematode parasites exposed to different anthelmintic drugs. This technique, a well proven tool for assessing the time evolution of different phenomena, is here successfully used to quantify parasite motility in pharmacodynamic assays. The characterization of the pharmacological properties of anthelmintic drugs is critical to optimize their use in parasite control. Besides, the evaluation of nematode motility is a relevant indicator of the pharmacodynamic effect of anthelmintic drugs. The application of this approach to study the motility of Haemonchus contortus (used as a model of nematode parasites) larvae exposed to different drugs is presented, showing its usefulness.Abbreviations ABZ albendazole - BZD benzimidazole - IVM ivermectin - LVM levamisole     

Increased surfactant protein A content in human alveolar macrophages in hypersensitivity pneumonitis.

Surfactant protein A (SP-A) appears to have an important function in the assembly and maintenance of the alveolar surfactant monolayer. SP-A has also been implicated in modulating the activity of immunoactive cells, such as increasing the bactericidal capacity of alveolar macrophages. In this immunocytochemical study the SP-A content of alveolar macrophages from seven patients with hypersensitivity pneumonitis was compared with the results obtained from six healthy controls. A polyclonal rabbit antibody against human SP-A was used for detection of SP-A in the cytoplasm of alveolar macrophages, applying the immunoperoxidase adhesive slide assay. In hypersensitivity pneumonitis a significant increase in the percentage of SP-A+ alveolar macrophages was observed as compared with the percentage in healthy controls. The intensity of the staining reaction was also increased in the alveolar macrophages of hypersensitivity pneumonitis. We conclude that the observed abnormalities in SP-A content in alveolar macrophages may play a role in the pathogenesis of hypersensitivity pneumonitis.     

Role of nitric oxide in murine cytomegalovirus (MCMV) infection

Cytomegalovirus (CMV) is a typical pathogen of an opportunistic infection. In this review article, various roles of nitric oxide (NO) in murine CMV (MCMV) infections, including acute, persistent and latent infections, are discussed. In the acute phase of MCMV infection, NO plays a protective role against MCMV infection. In contrast, NO has been proven to act as a pathogenic factor in a model of MCMV pneumonitis. In MCMV persistent infection, when MCMV was detected only in the salivary gland, T cells of mice were modified to produce a massive amount of such cytokines as TNF-alpha and IFN-gamma upon in vivo stimulation with anti-CD3. These cytokines then induced mRNA for inducible NO synthase (iNOS), thus resulting in the production of a large amount of NO. A histochemical study demonstrated that NO damaged bronchial epithelial cells, and thereby apparently inducing pneumonitis. In the case of a latent infection, when viral DNA was detected in the host in spite of the absence of any infectious particle, NO increased the amount of persistently-infected MCMV-DNA. As a result, NO was found to act as "a double edged sword" in the CMV-host relationship.     

Effects of Proton Pump Inhibitors on Lung Cancer Precise Radiotherapy-Induced Radiation Pneumonitis

The objective of this study was to explore the effects of proton pump inhibitors (PPIs) on the development and prognosis of lung cancer precise radiotherapy-induced radiation pneumonitis. Clinical materials of 84 lung cancer patients who had radiation pneumonitis after precise radiotherapy were retrospectively analyzed, and the patients were divided into PPI group and control group, according to whether or not PPIs were applied. The development and prognosis of patients and the effects of different doses of PPI on patient condition from two groups were compared. There were 57 PPI cases in PPI group and 27 cases in control group. Basic characteristics of patients were not statistically different between the two groups; however, white blood cell count, oxygenation indexes, blood gas pH, and lung imaging index were significantly different (p < 0.05), indicating that radiation pneumonitis tended to be more severe in PPI group. As regards effects of PPI on prognosis of two groups, remission rate of radiation pneumonia in PPI group was significantly less than that of the control group. Among 57 cases in PPI group, there were 31 patients applied with PPI ≤ 1DDD and 31 patients applied with PPI > 1DDD. In comparison of the various parameters of patients, 7 days after being applied with different doses of PPI, there were no significant differences between the parameters of radiation pneumonitis. PPIs should be cautiously utilized to avoid the effects of lung cancer radiotherapy-induced radiation pneumonia.     

Pulmonary Toxicity of Antineoplastic Agents

Pulmonary parenchymal or pleural reactions to chemotherapeutic agents used in the management of patients with malignant diseases are being recognized with increasing frequency. Alkylating agents, asparaginase, bleomycin, methotrexate and procarbazine have all been implicated. Some of the reactions, such as the rare procarbazine pleuritis and pneumonitis, represent hypersensitivity phenomena. Others, such as alkylating agent pulmonary toxicity, appear to be direct toxic effects of the drugs. The severity of the toxicity is variable. The appearance of these pulmonary changes must be differentiated from tumor progression or a variety of possible infections. The awareness of possible pulmonary toxicity is of great importance since early discontinuation of the agent following the first hint of pulmonary toxicity may allow partial or complete reversal of the process. Continued therapy in the face of drug-related pulmonary toxicity may enhance the likelihood of irreversible pulmonary compromise with respiratory failure and death.     

Nonbacterial pneumonitis with multidrug antineoplastic therapy in breast carcinoma

Seventeen patients with metastatic breast carcinoma were treated with a combination of 5-fluorouracil, methotrexate, vincristine, cyclophosphamide and prednisone. Six of the patients (35%) developed a syndrome consisting of fever, malaise, dyspnea, hypoxemia and bilateral pulmonary interstitial infiltrates from 41 to 148 days after institution of therapy. The syndrome varied from a mild to a life-threatening illness with recovery in 10 to 60 days. It is believed that these cases represent examples of methotrexate-induced pneumonitis. The high incidence of the syndrome in this patient group may be related to the concomitant administration of cyclophosphamide with methotrexate. The observations also suggest that patients with previous adrenalectomies may have pneumonitis with an especially severe and protracted course.     

A case of fire-eater's pneumonia in an active-duty soldier

Fire-eater's pneumonia is an acute, intense hydrocarbon pneumonitis resulting from aspiration of volatile hydrocarbons such as kerosene, gasoline, or turpentine. The vast majority of patients have resolution of their acute lung injury with supportive care only, avoiding the need for surgical lung reduction procedures. We describe a case of severe hydrocarbon pneumonitis secondary to aspiration of JP-8 jet fuel. The presentation, management, and prognosis of fire-eater's pneumonia are reviewed.     

Protective effect of corticosteroids on radiation pneumonitis in mice

We explored the protective effect of corticosteroids on the mortality of mice that received thoracic irradiation. Methylprednisolone, 100 mg/kg/week, given from 11 weeks after gamma irradiation of the thorax resulted in an increase in the LD50 (11-26 weeks) from 14.3 +/- 0.3 (mean +/- SE) Gy to 17.6 +/- 0.4 Gy, P less than 0.001, a protection factor of 1.2. Withdrawal of steroids at various times during the period of radiation pneumonitis resulted in accelerated mortality in the next 2-4 weeks, so that the cumulative mortality "caught up" with that of control animals by 4 weeks after steroid withdrawal. However, after the end of the usual period of pneumonitis withdrawal of steroids did not result in accelerated mortality, suggesting that the time when steroids are protective corresponds to the duration of pneumonitis. A smaller dose of steroids, 25 mg/kg/week, was found to be as protective as the larger dose used in the above experiments. The possibility that corticosteroids reduce mortality, even when given many weeks after radiation, may have important practical and theoretical implications.     

¿Necesitamos nuevos tratamientos para la diabetes tipo 2?

Diagnosis of type 2 diabetes mellitus encompasses multiple pathophysiological and clinical situations. Type 2 diabetes mellitus is characterized by a long and changing natural history. Personal circumstances and preferences also condition the actual effectiveness and safety of drugs used. In recent decades, modern drugs have markedly expanded and improved therapeutic options. However, their effectiveness remains limited in clinical practice. The main objective of decreasing macrovascular complications is not fully proven. Adverse events, especially hypoglycemia and weight gain, are still frequent and decrease treatment adherence. The constant loss of endogenous islet cell reserve is the main determinant of the need for intensified therapies. Current treatments have failed to improve long-term beta cell mass/function. It is desirable to move forward to obtain new drugs that offer solutions sustainable in the long term. These drugs should be able to fit the individual circumstances and preferences of patients with diabetes mellitus.     

Modulation of the LDL receptor and LRP levels by HIV protease inhibitors

Inhibitors of the human immunodeficiency virus (HIV)-1 protease have proven to be effective antiretroviral drugs. However, patients receiving these drugs develop serious metabolic abnormalities, including hypercholesterolemia. The objective of the present study was to identify mechanisms by which HIV protease inhibitors increase plasma cholesterol levels. We hypothesized that HIV protease inhibitors may affect gene regulation of certain LDL receptor (LDLR) family members, thereby altering the catabolism of cholesterol-containing lipoproteins. In this present study we investigated the effect of several HIV protease inhibitors (ABT-378, Amprenavir, Indinavir, Nelfinavir, Ritonavir, and Saquinavir) on mRNA, protein, and functional levels of LDLR family members. Our results demonstrate that one of these drugs, Nelfinavir, significantly decreases LDLR and LDLR-related protein (LRP) mRNA and protein levels, resulting in the reduced functional activity of these two receptors. Nelfinavir exerts its effect by reducing levels of active SREBP1 in the nucleus. The finding that Nelfinavir reduces the levels of two key receptors (LRP and LDLR) involved in lipoprotein catabolism and maintenance of vessel wall integrity identifies a mechanism that causes hypercholesterolemia complications in HIV patients treated with this drug and raises concerns about the atherogenic nature of Nelfinavir.     

Debate: Do all patients with heart failure require implantable defibrillators to prevent sudden death?

Sudden death is a major cause of mortality in patients with ventricular dysfunction. The highest risk occurs among patients with less severe functional impairment. Current methods of risk stratification are inadequate, and a rational therapy for prevention of sudden death is not available. The implantable cardioverter-defibrillator (ICD) has proven to be more effective than drugs in reducing sudden-death risk in some subsets of patients. Empiric ICD therapy, targeting the general population with mild to moderate heart failure, will maximize the impact of such a strategy to prevent sudden death and improve long-term survival.