Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury.

BACKGROUND: Genotoxic stress, such as by exposure to bromodeoxyuridine (BrdU) and cigarette smoke, induces premature cell senescence. Recent evidence indicates that cellular senescence of various types of cells is accelerated in COPD patients. However, whether the senescence of airway epithelial cells contributes to the development of airway diseases is unknown. The present study was designed to test the hypothesis that premature senescence of airway epithelial cells (Clara cells) impairs repair processes and exacerbates inflammation after airway injury. METHODS: C57/BL6J mice were injected with the Clara-cell-specific toxicant naphthalene (NA) on days 0, 7, and 14, and each NA injection was followed by a daily dose of BrdU on each of the following 3 days, during which regenerating cells were allowed to incorporate BrdU into their DNA and to senesce. The p38 MAPK inhibitor SB202190 was injected 30 minutes before each BrdU dose. Mice were sacrificed at different times until day 28 and lungs of mice were obtained to investigate whether Clara cell senescence impairs airway epithelial regeneration and exacerbates airway inflammation. NCI-H441 cells were induced to senesce by exposure to BrdU or the telomerase inhibitor MST-312. Human lung tissue samples were obtained from COPD patients, asymptomatic smokers, and nonsmokers to investigate whether Clara cell senescence is accelerated in the airways of COPD patients, and if so, whether it is accompanied by p38 MAPK activation. RESULTS: BrdU did not alter the intensity of the airway epithelial injury or inflammation after a single NA exposure. However, after repeated NA exposure, BrdU induced epithelial cell (Clara cell) senescence, as demonstrated by a DNA damage response, p21 overexpression, increased senescence-associated ß-galactosidase activity, and growth arrest, which resulted in impaired epithelial regeneration. The epithelial senescence was accompanied by p38 MAPK-dependent airway inflammation. Senescent NCI-H441 cells impaired epithelial wound repair and secreted increased amounts of pro-inflammatory cytokines in a p38 MAPK-dependent manner. Clara cell senescence in COPD patients was accelerated and accompanied by p38 MAPK activation. CONCLUSIONS: Senescence of airway epithelial cells impairs repair processes and exacerbates p38 MAPK-dependent inflammation after airway injury, and it may contribute to the pathogenesis of COPD.

[Sustainable efficacy of oral varenicline for smoking cessation].

Varenicline (Champix) is an alpha4beta2 nicotinic receptor antagonist that is used orally for treatment of nicotine dependence. We conducted a study to examine the sustainable efficacy of varenicline in smoking cessation. The subjects were 148 outpatients (113 men, 35 women; average age; 54.4 +/- 14.0 years) at 6 different hospitals, and their adverse events were monitored in each hospital. The 4-week continuous abstinence rates of smoking cessation were 17.6%, 75.0%, and 84.6% in groups treated for 4 or fewer weeks, 5 to 8 weeks, and 9 to 12 weeks, respectively, with the rate showing a significant increase according to treatment period. Among 83 patients who had adverse events, the abstinence rates were 76.9%, 92.3%, 54.5%, and 55.6% in an observed (OB) group, a nosotropic medication (NM) group, a dose-reduction (RD) group, and a drug-discontinuation (DC) group, respectively. Among 56 patients with nausea, the respective rates were 80.8%, 100.0%, 61.1%, and 50.0%, respectively, with a significantly higher success rate in the NM group than in the RD or DC groups (each p < 0.05). To sustain the efficacy of varenicline in patients with adverse events, we recommend a therapeutic strategy in which the active nosotropic medicine is administered over 12 weeks at the regular dosage.

Therapeutic effects of erythropoietin in murine models of endotoxin shock.

OBJECTIVE: Erythropoietin has recently emerged as a cytoprotective cytokine, which possesses the ability to protect many tissues, including the brain, heart, and kidneys, against ischemia or traumatic injury. We investigated the therapeutic effects of erythropoietin in a murine model of endotoxin shock. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: Male BALB/c mice. INTERVENTIONS: Mice intraperitoneally received either lipopolysaccharide (LPS) from Escherichia coli or vehicle. Erythropoietin was administered at a dose of 1000 IU/kg subcutaneously at different time points after LPS administration. We also investigated the effect of erythropoietin on the development of septic shock caused by cecal perforation. MEASUREMENTS AND MAIN RESULTS: Treatment of mice with erythropoietin, within 2 hours after LPS administration, improved the mortality rate. Treatment of cecal perforated mice with erythropoietin extended survival by 12 hours, but all animals died by 72 hours in both groups. Erythropoietin attenuated apoptosis in the lungs, liver, small intestine, thymus, and spleen, as assessed by terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling staining, active caspase-3 immunostaining and immunoblotting, and measurements of caspase-3/7 activity. Erythropoietin also reduced inducible nitric oxide synthase expression, nitric oxide production, peroxynitrite formation, and tissue hypoxia. In contrast, erythropoietin did not affect the degree of LPS-induced inflammation, as assessed by measurements of blood levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, growth-related oncogene/keratinocyte-derived cytokine, and high mobility group box 1, the phosphorylation levels of nuclear factor kappaB, and the number of neutrophils infiltrating the lungs and the liver. CONCLUSIONS: The results of the study demonstrate that administration of a large dose of erythropoietin after induction of experimental endotoxemia improved survival and that the beneficial effects of erythropoietin were associated with inhibition of apoptosis, nitric oxide production, and tissue hypoxia, without alterations in inflammatory responses.

Platinum nanoparticle antioxidants inhibit pulmonary inflammation in mice exposed to cigarette smoke.

Recent evidence implicates increased oxidative stress as an important mechanism of the pulmonary inflammation that occurs in cigarette smokers. Since cigarette smoke (CS) contains and generates a large amount of reactive oxygen species (ROS) that elicit pulmonary inflammation, antioxidants may become effective therapeutic agents for CS-related inflammatory lung diseases, such as chronic obstructive pulmonary disease. Platinum nanoparticles stabilized with polyacrylate to form a stable colloid solution (PAA-Pt) are a new class of antioxidants that has been shown to efficiently quench ROS. In the present study we investigated the therapeutic effects of PAA-Pt on pulmonary inflammation in smoking mice. PAA-Pt or saline was administered intranasally to DBA/2 mice, which were then exposed to CS or control air daily for 3 days. Mice were sacrificed 4h after their final exposure to CS or control air. CS exposure caused depletion of antioxidant capacity, NFkappaB activation, and neutrophilic inflammation in the lungs of mice, and intranasal administration of PAA-Pt prior to CS exposure was found to inhibit these changes. Intranasal administration of PAA-Pt alone did not elicit pulmonary inflammation or toxicity. In in vitro experiments, treatment of alveolar-type-II-like A549 cells with PAA-Pt inhibited cell death after exposure to a CS extract. These results suggest that platinum nanoparticles act as antioxidants that inhibit pulmonary inflammation induced by acute cigarette smoking.

[Severe case of Tsutsugamushi disease with disseminated intravascular coagulation and acute respiratory distress syndrome].

A 65-year-old man was admitted because of high grade fever and cough after 3 days of gathering edible wild plants. Although ceftriaxone was given to him, his symptoms did not improve. His high grade fever escalated after changing the antibiotics (imipenem with erythromycin). His situation further declined with disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). As a result, he was transferred to the Department of Respiratory Medicine 7 days after admission. He was intubated and placed on mechanical ventilation and treated by polymyxin-direct hemoperfusion. The eschar on his chest wall caused us to suspect Tsutsugamushi disease and a blood test confirmed our suspicion. Since the antibodies for Tsutsugamushi were elevated we arrived at the diagnosis of Tsutsugamushi disease with DIC and ARDS. The administration of tetracycline was sufficient to significantly improve his condition. Because its complications are life threatening, when we see a patient with fever and eruptions, it is necessary to keep in mind the possibility of Tsutsugamushi disease. Careful anamnesis and physical examinations are most important for the diagnosis of Tsutsugamushi disease.

[Case of loxoprofen sodium-induced eosinophilic pneumonia that occurred ipsilaterally after VATS lobectomy for lung cancer].

A 76-year-old man was admitted because of dry cough and dyspnea two weeks after VATS lobectomy for lung cancer. Chest radiographs and computed tomography showed interstitial shadows in the only operative lung side. Although antibiotic drugs were given because we believed it to be postoperative pneumonia, abnormal shadows on chest radiographs increased. A bronchoalveolar lavage fluid (BALF) study performed on the 21" day after operation showed that the proportions of eosinophils, basophils and mast cells had increased, and the CD4/CD8 ratio was 4.42. The drug lymphocyte stimulation test for loxoprofen sodium was positive. Based on the clinical course, laboratory data and BALF study, we arrived at a diagnosis of drug-induced pneumonia caused by loxoprofen sodium. Treatment with corticosteroid resulted in marked improvement of the chest radiographs and clinical findings. Drug-induced pneumonia usually occurs bilaterally, but it occurred only on the operative side in this case. Although rare, it is important to recognize that unilateral drug-induced pneumonia is one of the differential diagnose of postoperative pneumonia.

Estimation of parasympathetic nerve function during sleep in patients with obstructive sleep apnea by instantaneous time-frequency analysis.

BACKGROUND AND OBJECTIVES: The pathophysiologic aspects of parasympathetic nerve (PN) function during sleep in patients with obstructive sleep apnea (OSA) studied by classical power spectrum analysis on heart rate variability (HRV) are highly controversial. The controversy is attributed to methodologic concerns, such as poor time resolution involved in power spectrum analysis. We aimed to establish the appropriate method for the investigation of PN function in OSA patients with apneas and hypopneas using instantaneous time-frequency analysis with complex demodulation (CD) and sufficient time resolution. METHODS: A total of 30 patients with PSG-confirmed mild to severe OSA were recruited for the analysis of frequency spectra contained in R-R intervals (RRI) of overnight electrocardiograph (ECG) tracings. High-frequency (HF) domains ranging between 0.15 and 0.40 Hz were selected for analysis. Among these domains, the HF domain with the maximum instantaneous amplitude was defined as the main HF peak and was used as the surrogate marker of PN discharge. Based on density spectrum array (DSA) map for main HF peak constructed with a time scale of 1s and a frequency resolution of 0.002 Hz (HF-DSA map), the shift in central frequency (CF) of main HF peak over time was continuously monitored. When the main HF peak with the same CF lasted for more than 20 s or 5 min on HF-DSA map, the PN function was considered to be stable or very stable. The measurements were then repeated after continuous positive airway pressure (CPAP) treatment. RESULTS: The extent of PN-evoked modulation of RRI was enhanced in nonrapid eye movement (NREM) sleep, though the stability was reduced in both NREM and rapid eye movement (REM) sleep. These peculiar behaviors of PN function were reversed by CPAP treatment. CONCLUSION: We found that instantaneous time-frequency analysis allowed estimation of transitional changes in PN function during sleep in OSA patients.

Novel regression equations predicting lung age from varied spirometric parameters.

Although lung age calculated backward from regression formulas constructed for FEV(1) estimation is widely used, it possesses a couple of faults. We developed novel equations predicting lung age from varied spirometric parameters (spirometry-derived lung age (SDL-age)). Applying multiple regression analysis, equations predicting SDL-age were invented using data from 8015 never-smokers with normal spirometry (group I). Validation was made based on data from 6398 never-smokers with normal spirometry (group II). Equations were further applied for 446 subjects with airflow limitation. FEV(1), FEV(1)/FVC, FEF(50), and PEF were selected as explanatory variables for reference value of SDL-age. Normal limits of difference between SDL-age and chronological-age were ± 13.4 years in the male and ± 15.0 years in the female. Established equations predicted SDL-age of group II. SDL-age was older than chronological-age only in subjects with severe airflow limitation. Novel regression equations allowing prediction of reference value of SDL-age and normal limits of difference between SDL-age and chronological-age were elaborated in both genders.

How to evaluate "spirometric" lung age--what method is approvable?

The method predicting lung age was originally proposed by Morris and Temple (1985). In their method, lung age was estimated by counting back the regression formula predicting normal value of FEV1. Since the normal value of FEV1 at a given age is not unique and exists within a certain range defined as 95% confidence interval, the backward value of lung age calculated with the original method includes statistical and physiological problems. Analyzing the problems related to the original method, we have developed a novel method with revising age-elicited variation in FEV1. When the original method is applied, the lung age of a person with measured FEV1 beyond upper-limit-of-normal (ULN) results in being remarkably young (sometimes, below zero), while that of a person with FEV1 below lower-limit-of-normal (LLN) is estimated as being very elderly (sometimes, over 100). On the other hand, the novel method, in which age-related variation in FEV1 is reliably corrected, predicts a wide range of lung age even when measured FEV1 is significantly above ULN or below LLN.