Earthworm extract attenuates silica-induced pulmonary fibrosis through Nrf2-dependent mechanisms.

Silicosis is an occupational pulmonary fibrosis caused by inhalation of silica (SiO2) and there are no ideal drugs to treat this disease. Earthworm extract (EE), a natural nutrient, has been reported to have anti-inflammatory, antioxidant, and anti-apoptosis effects. The purpose of the current study was to test the protective effects of EE against SiO2-induced pulmonary fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. We found that treatment with EE significantly reduced lung inflammation and fibrosis and improved lung structure and function in SiO2-instilled mice. Further mechanistic investigations revealed that EE administration markedly inhibited SiO2-induced oxidative stress, mitochondrial apoptotic pathway, and epithelial-mesenchymal transition in HBE and A549 cells. Furthermore, we demonstrate that Nrf2 activation partly mediates the interventional effects of EE against SiO2-induced pulmonary fibrosis. Our study has identified EE to be a potential anti-oxidative, anti-inflammatory, and anti-fibrotic drug for silicosis.

Toxicity study of mineral medicine haematitum.

ETHNOPHARMACOLOGICAL RELEVANCE: Haematitum, a time-honored mineral-based Chinese medicine, has been used medicinally in China for over 2000 years. It is now included in the Chinese Pharmacopoeia and used clinically for treating digestive and respiratory diseases. The Chinese Materia Medica records that it is toxic and should not be taken for a long period, but there are few research reports on the toxicity of Haematitum and its potential toxicity mechanisms. AIM OF THE STUDY: This study aimed to evaluate the toxicity of Haematitum and calcined Haematitum, including organ toxicity, neurotoxicity, and reproductive toxicity. Further, it is also necessary to explore the mechanism of Haematitum toxicity and to provide a reference for the safe clinical use of the drug. MATERIALS AND METHODS: The samples of Haematitum and calcined Haematitum decoctions were prepared. KM mice were treated with samples by gavage for 10 days, and lung damage and apoptosis were assessed by HE staining and TUNEL staining of lung tissues respectively. Metabolomics analysis was performed by HPLC-MS. Metallomics analysis was performed by ICP-MS. In addition, C. elegans was used as a model for 48 h exposure to examine the neurotoxicity and reproductive toxicity-related indices of Haematitum, including locomotor behaviors, growth and development, reproductive behaviors, AChE activities, sensory behaviors, apoptosis, and ROS levels. RESULTS: The use of large doses of Haematitum decoction caused lung damage in mice. Neither calcined Haematitum decoction nor Haematitum decoction at clinically used doses showed organ damage. Metabolomics results showed that disorders in lipid metabolic pathways such as sphingolipid metabolism and glycerophospholipid metabolism may be important factors in Haematitum-induced pulmonary toxicity. High doses of Haematitum decoction caused neurological damage to C. elegans, while low doses of Haematitum decoction and calcined Haematitum decoction showed no significant neurotoxicity. Decoction of Haematitum and calcined Haematitum did not show reproductive toxicity to C. elegans. Toxicity was also not observed in the control group of iron (Ⅱ) and iron (Ⅲ) ions in equal amounts with high doses of Haematitum. CONCLUSIONS: Haematitum is relatively safe for routine doses and short-term use. Calcination can significantly reduce Haematitum toxicity, and this study provides a reference for safe clinical use.

[Cardiac involvement in adults with echinococcosis].

Experiments have established that the first target for echinococcus is the liver and lung and that for pathogenic fungi and protozoa is the heart. Adult patients with hepatic hydatid disease complicated by paecilomycosis have been found to have atypical paecilomycosis-associated myocarditis, the treatment of which was developed by the authors, by using antibiotics, fungicides, and homeopathic remedies.

[Effect of Limax lyophilized powder on bronchial asthma].

OBJECTIVE: To study the effect of Limax lyophilized powder on bronchial asthma. METHODS: The allergic asthma model was established in guinea pigs by combined utilization of aluminum hydroxide and egg albumin to investigate the effect of Limax lyophilized powder on the bronchial flow and on the level of inflammator in bronchoalveolar lavage and serum. RESULTS: The mortality of asthma laboratory guinea pigs was reduced and the incubation period of asthma was extended significantly in Limax lyophilized powder groups. Its antiasthmatic effect was as efficient as the control drug (aminophylline). The leucocyte count was decreased in peripheral blood and the bronchoalveolar lavage fluid. The infiltration of pulmonary tissues eosinophil was also significantly reduced. Further more,the most efficient effects was showed in Limax lyophilized powder at the moderate dosage (63 mg/kg). The bronchial perfusion flow was increased and the level of IL-2 and IL-4 in blood serum and bronchoalveolar lavage fluid was decreased obviously in the aminophylline group and Limax lyophilized powder groups at moderate and high dosage. CONCLUSION: Limax lyophilized powder could inhibit bronchial asthma evidently.

The Protective Effect of Chrysanthemum indicum Extract against Ankylosing Spondylitis in Mouse Models.

In traditional Chinese and Korean homeopathic medicine, Chrysanthemum indicum Linné (Asteraceae) is a time-honored herb, prescribed for the resolution of symptoms associated with inflammatory and hypertensive conditions as well as those affecting the lungs and its associated structures. The goal of this work is to investigate the defensive role of Chrysanthemum indicum extract in fighting ankylosing spondylitis (AS) using mouse models, through which the manifestation and extent of the disease progression were measured with quantitative analysis of the intervertebral joints. Markers of inflammation as well as oxidative stress were also analysed. Western blot was used to quantify the levels of Nuclear Factor-κB (NF-κB) p65, Dickkopf-1 (DKK-1), and sclerostin (SOST). Consequently, the findings of this experiment demonstrated that AS in mice that were given Chrysanthemum indicum extract had lower level of TNF-α, IL-1ß, and IL-6 (P < 0.05) and increased level of catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) (P < 0.05). The results also revealed that Chrysanthemum indicum supplemented with diet contributed to a decrease in Nuclear Factor-κB (NF-κB) p65 protein expression (P < 0.05) and higher levels of DKK-1 and SOST proteins (P < 0.05). Therefore, we concluded that the beneficial role of Chrysanthemum indicum in AS is manifested through downregulating oxidative stress, inhibiting inflammatory mediators and NF-κB, and increasing DKK-1 and SOST levels.

Continuous skeletal muscle paralysis: effect on neonatal pulmonary mechanics.

Pancuronium bromide (Pavulon) is used to induce skeletal muscle paralysis in preterm infants, presumably for effective ventilatory support during acute respiratory failure. Twelve infants with respiratory failure were evaluated for sequential changes in pulmonary mechanics during continuous pancuronium administration (0.1 mg/kg every two to three hours) for more than 48 hours. The study weight of the neonates ranged from 980 to 2,950 g, and the postconceptional age ranged from 27 to 41 weeks. Pulmonary compliance, resistance, and resistive work of breathing were determined, using least mean square analysis technique, daily for three days and after discontinuation of pancuronium (even though there was no clinical improvement in ventilatory management). The dynamic pulmonary compliance decreased from 0.38 +/- 0.05 to 0.30 +/- 0.04 mL/cm H2O/kg (mean +/- SE) (P less than .05) and the total pulmonary resistance increased 51% from 115.6 +/- 21.3 to 174.9 +/- 27.3 cm H2O/L/s (P less than .005) during prolonged skeletal muscle paralysis. Upon discontinuation of pancuronium, the dynamic pulmonary compliance increased 43% to 0.43 +/- 0.4 mL/cm H2O/kg (P less than .05) and the total pulmonary resistance decreased by 41% (P less than .005). These data question the advisability of prolonged skeletal muscle paralysis in neonates and suggest the need for further detailed evaluation of the effects of prolonged paralysis on neonatal pulmonary mechanics.

Pancuronium and gallamine are antagonists for pre- and post-junctional muscarinic receptors in the guinea-pig lung.

The effects of atropine, pancuronium and gallamine were tested on pre- and post-junctional muscarinic receptors in the lung. Inhibition of bronchoconstriction induced by intravenous injection of acetylcholine (ACh) was used as a measure of post-junctional receptor blockade. All three antagonists reduced ACh-induced bronchoconstriction. The effects were dose-related for atropine and pancuronium and complete inhibition was obtained with 0.01 mg/kg and 10 mg/kg respectively. Gallamine was much less potent than the other two drugs; the inhibitory effect was not dose-related and never exceeded 50% even at a dose of 10 mg/kg. In contrast, blockade of pre-junctional inhibitory muscarinic receptors in pulmonary parasympathetic nerves by these three antagonists, produced potentiation of bronchoconstriction induced by vagal-nerve stimulation. Consequently, the effect of the three antagonists on vagally-induced bronchoconstriction is dependent on the balance between their pre- and post-junctional blocking activity. Gallamine was the most effective and atropine the least effective antagonist for potentiating nerve-induced bronchoconstriction. At doses which produce 100% neuromuscular blockade, both pancuronium (0.04 mg/kg) and gallamine (4 mg/kg) potentiated vagally-induced bronchoconstriction. At these doses, pancuronium doubled and gallamine caused a four-fold increase in vagally-induced bronchoconstriction, despite partial concurrent blockade of muscarinic receptors in the smooth muscle of the airways.

Differential effects of pancuronium bromide on cardiopulmonary function in the neonatal lamb.

The effect of pancuronium bromide (Panc Br) on resting cardiopulmonary function and cardiopulmonary responses to intravenous injection of acetylcholine (Ach) and histamine (H) was evaluated in neonatal lambs. The animals were mechanically ventilated and managed to maintain physiologic gas exchange and acid-base conditions. A proximal segment of the cervical trachea was bypassed; the developed pressure response of this segment (P cervical trach) was used as a direct indication of airway smooth muscle contraction and bronchoconstriction. Pulmonary resistance (Rp) and functional residual capacity were determined. The change in Rp from resting values was used as a functional indicator of central and peripheral airway bronchoconstriction. Cardiovascular function and responses were evaluated from changes in mean arterial pressure and heart rate. Following Panc Br, there was a significant reduction in Ach-induced P cervical trach (-50 +/- 9.2% SE) and Rp (-46 +/- 2.4% SE). In contrast, Panc Br did not significantly change Ach-induced bradycardia and hypotension, cardiopulmonary responses to H, and resting cardiopulmonary function. The differential effects of Panc Br on cardiopulmonary function appear to be related to regional differences between cardiovascular and airway smooth muscle muscarinic receptors in the neonate. The results of this study elucidate a mechanism which may explain previously reported variability in the effect of Panc Br on neonatal cardiopulmonary function. Furthermore, the Panc Br-related attenuation of airway smooth muscle responses suggests that this form of neuromuscular blockade affects the regulation of airway tone and may influence the susceptibility of the neonate to airway deformation consequent to mechanical ventilation.

Antitussive activity of Anar.

Affinity-purified antibodies to morphine (mixture of homeopathic dilutions C30+C200) produced an antitussive effect on male and female guinea pigs with cough induced by citric acid and capsaicin.

Neuromuscular blockade and lung function during resuscitation of infants with congenital diaphragmatic hernia.

BACKGROUND: There is no consensus or evidence as to whether a neuromuscular blocking agent should be used during the initial resuscitation of infants with congenital diaphragmatic hernia (CDH) in the labour ward. OBJECTIVE: To determine if administration of a neuromuscular blocking agent affected the lung function of infants with CDH during their initial resuscitation in the labour ward. METHODS: Fifteen infants with CDH were studied (median gestational age 38 weeks, range 34-41; birth weight 2,790 g, range 1,780-3,976). Six infants had undergone feto-endotracheal occlusion (FETO). Flow, airway pressure, tidal volume and dynamic lung compliance changes were recorded using a respiratory function monitor (NM3, Respironics). Twenty inflations immediately before, immediately after and 5 min after administration of a neuromuscular blocking agent (pancuronium bromide) were analysed. RESULTS: The median dynamic lung compliance of the 15 infants was 0.22 ml/cm H2O/kg (range 0.1-0.4) before and 0.16 ml/cm H2O/kg (range 0.1-0.3) immediately after pancuronium bromide administration (p < 0.001) and remained at a similar low level 5 min after pancuronium bromide administration. The FETO compared to the non-FETO infants had a lower median dynamic compliance both before (p < 0.0001) and 5 min after pancuronium administration (p < 0.001) and required significantly longer durations of ventilation (p = 0.004), supplementary oxygen (p = 0.003) and hospitalisation (p = 0.007). CONCLUSIONS: Infants with CDH, particularly those who have undergone FETO, have a low lung compliance at birth, and this is further reduced by administration of a neuromuscular blocking agent.

Investigating lung remodeling in Modul8-treated BALB/c asthmatic animals.

Animal models of bronchial hyperresponsiveness have been successfully used to investigate the pathophysiology of asthma. When mice are sensitized and challenged with an allergen, such as OVA, they experience symptoms and processes similar to that of humans, and are therefore widely used as asthmatic animal models. In the current study the BALB/c murine asthmatic animal model was used to investigate the histological and ultrastructural changes that occur in the lungs of asthmatic animals that received no treatment, compared to two groups of asthmatic animals that were treated with a homeopathic immunodulator Modul8 and hydrocortisone as positive control, respectively. Eosinophil counts in the bronchial lavage of the animals were also analyzed, since it is known that eosinophil counts are increased in the bronchial lavage in asthma. Results indicated that eosinophil counts were elevated in asthmatic animals compared to the controls, but were found to be significantly decreased in the treatment groups. Also, in the asthmatic, untreated animals, histological and ultrastructural changes, typically associated with the inflammatory process were found. Both treatment groups compared well to that of the control animals, indicating that the homeopathic product might be successfully used in the treatment of asthma.

Pulmonary function following 'pretreatment' dose of pancuronium in volunteers.

The effect of a pretreatment dose (0.014 mg/kg) of pancuronium bromide on pulmonary function tests in 15 healthy volunteers was investigated. Ventilatory flow volume loops and maximum voluntary ventilation were determined before and 1 and 3 minutes following administration of the pancuronium. Calculation of the pulmonary function from the flow volume loops revealed statistically significant decreases in forced expiratory flow at 50% of expired volume, forced expiratory volume at 1 second and 3 seconds, peak inspiratory flow, peak inspiratory flow at 50% of inspired volume, forced vital capacity, and maximum voluntary ventilation. Significant pulmonary dysfunction associated with dyspnea was seen in four subjects and one subject had to be artificially ventilated and pancuronium had to be reversed with prostigmine. Ventilation should be closely monitored in patients following pretreatment doses of pancuronium in view of frequent atypical responses.

Pancuronium during mechanical ventilation speeds recovery of lungs of infants with hyaline membrane disease.

Spontaneous breathing during mechanical ventilation in newborn infants may damage the lung. To find out whether the prevalence of lesions which might be due to trauma was reduced by muscle relaxation, fifty infants who required mechanical ventilation of hyaline membrane disease were randomly assigned to treated and control groups. The treated infants were kept muscle relaxed with pancuronium bromide until they needed a FiO2 of 0.40 or less during ventilation. The mean birthweight, gestational age, age at entry to the trial, duration of intubation and ventilation, FiO2 during the acute phase of the illness, and ventilator pressures were closely comparable in the two groups. Two of twenty-six treated infants and one of twenty-four controls died. Four treated and five control infants acquired pneumothoraces and/or interstitial emphysema. The length of time that the treated infants required added oxygen was significantly less than in the control infants. All treated infants were breathing room air spontaneously by one month of age whereas seven control infants were still dependent on added oxygen, needing an average FiO2 of 0.35 to achieve a mean PaO2 of 6.5 kPa (49 mm Hg). These seven infants required added oxygen until they were 5-18 (mean 10) weeks old. Muscle relaxation during mechanical ventilation for hyaline membrane disease speeds recovery of the lungs, probably owing to a reduction in traumatic damage.

Pretreatment with non-depolarizing muscle relaxants: the influence on neuromuscular transmission and pulmonary function.

The influence of pretreatment with non-depolarizing muscle relaxants on the neuromuscular transmission was evaluated in 40 healthy, awake, non-premedicated volunteers using train-of-four (TOF) nerve stimulation and measurement of vital capacity (VC), inspiratory force (IF), peak expiratory flow (PEF), and forced expiratory volume in the first second (FEV1). The subjects were randomly allocated to one of four groups: group I received pancuronium 0.01 mg/kg; group II pancuronium 0.015 mg/kg; group III gallamine 0.3 mg/kg, and group IV gallamine 0.4 mg/kg intravenously. TOF ratio decreased significantly in groups II, III and IV but not in group I following precurarization. Median (25 and 75 percentiles) TOF ratios after pretreatment wer 94(92-96), 89 (86-93), 92 (89-93), and 93 (87-96), respectively. Overall there were decreases in VC, IF, and PEF, but only the decrease in PEF was statistically significant in all four groups. FEV1 was unchanged. The most pronounced decrease in VC, IF, and PEF (11, 29, and 29%, respectively) was seen one subject in group II with a TOF-ratio of 63 following precurarization. Four subjects (20%) in groups II and IV experienced difficulty in breathing. All subjects were, however, able to maintain head lift for more than 10 s, and none needed respiratory support. Seventy percent of all subjects had various minor complaints as, for instance, blurred vision and difficulty in swallowing. It is concluded that the higher doses of pancuronium 90.015 mg/kg) and gallamine (0.4 mg/kg) cannot be recommended for routine precurarization.

The interaction of neuromuscular relaxants with rabbit lung muscarinic receptors.

The interaction of muscle relaxants with airway muscarinic receptors of rabbit lung was investigated in vitro by the [3H]QNB binding technique. Pancuronium, vecuronium, alcuronium and succinyl choline chloride (SCC) inhibited the binding of [3H]QNB to rabbit lung muscarinic receptors in a dose-dependent manner. The values of IC50 (the concentration giving 50% inhibition) of pancuronium, vecuronium, alcuronium and SCC were 1.54 x 10(-5), 2.52 x 10(-5), 8.40 x 10(-5), and 4.00 x 10(-3) mol/l respectively. As the values of Kd increased with minimal change in the value of Bmax, while not influencing the number of receptors, these muscle relaxants had an inhibitory action on the affinity of muscarinic receptors to [3H]QNB in the order: pancuronium greater than or equal to vecuronium greater than alcuronium greater than SCC. Applying IC50 values to human conditions, clinical doses of these muscarinic relaxants are unlikely to exhibit any significant vagolytic action in lung tissue.