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Journal of Occupational Health Jan 2022We conducted inhalation and intratracheal instillation studies in order to examine the effects of tungsten trioxide (WO ) nanoparticles on the lung, and evaluated...
OBJECTIVES
We conducted inhalation and intratracheal instillation studies in order to examine the effects of tungsten trioxide (WO ) nanoparticles on the lung, and evaluated whether or not the nanoparticles would cause persistent lung inflammation.
METHODS
In the inhalation study, male 10-week-old Fischer 334 rats were classified into 3 groups. The control, low-dose, and high-dose groups inhaled clean air, 2, and 10 mg/m WO nanoparticles, respectively, for 6 h each day for 4 weeks. The rats were dissected at 3 days, 1 month, and 3 months after the inhalation, and the bronchoalveolar lavage fluid (BALF) and lung tissue were examined. In the intratracheal instillation study, male 12-week-old Fischer 334 rats were divided into 3 subgroups. The control, low-dose, and high-dose groups were intratracheally instilled 0.4 ml distilled water, 0.2, and 1.0 mg WO nanoparticles, respectively, dissolved in 0.4 ml distilled water. The rats were sacrificed at 3 days, 1 week, and 1 month after the intratracheal instillation, and the BALF and lung tissue were analyzed as in the inhalation study.
RESULTS
The inhalation and instillation of WO nanoparticles caused transient increases in the number and rate of neutrophils, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-2 in BALF, but no histopathological changes or upregulation of heme oxygenase (HO)-1 in the lung tissue.
CONCLUSION
Our results suggest that WO nanoparticles have low toxicity to the lung. According to the results of the inhalation study, we also propose that the no observed adverse effect level (NOAEL) of WO nanoparticles is 2 mg/m .
Topics: Male; Rats; Animals; Bronchoalveolar Lavage Fluid; Lung; Nanoparticles; Rats, Inbred F344; Water
PubMed: 36366872
DOI: 10.1002/1348-9585.12367 -
Antimicrobial Agents and Chemotherapy May 1994The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic...
The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(8) CFU of P. aeruginosa PA 508 prepared in agar beads. After 3 days, a single dose (300 micrograms) of free or liposome-encapsulated tobramycin was given intratracheally to both infected and uninfected rats. At various time intervals (0.25 to 16 h) after drug instillations, the remaining tobramycin was evaluated in blood, lungs, and kidneys by a microbiological assay. Intratracheal instillation of liposome-encapsulated tobramycin resulted in high and sustained levels of tobramycin in lungs of uninfected and infected rats over the 16-h period studied; however, the tobramycin levels were two times higher in uninfected rats. There was no tobramycin detected in the blood or kidneys from these animals. In contrast, the intratracheally instilled free tobramycin was cleared within 3 and 1 h from the lungs of uninfected and infected animals, respectively. These data suggest that the encapsulation of tobramycin in liposomes can result in a significant increase of its residence time within lungs. This study also shows that pulmonary infection was associated with a lowering of tobramycin levels in lungs.
Topics: Animals; Drug Carriers; Intubation, Intratracheal; Liposomes; Lung; Male; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Tobramycin
PubMed: 8067743
DOI: 10.1128/AAC.38.5.1090 -
Frontiers in Pharmacology 2022Exposure to water-soluble particulate matter (WPM) containing heavy metals can cause severe inflammatory responses and trigger and exacerbate the onset of asthma. As a...
Exposure to water-soluble particulate matter (WPM) containing heavy metals can cause severe inflammatory responses and trigger and exacerbate the onset of asthma. As a follow-up study of (RL), this study analyzed the therapeutic effects and mechanisms of oral and intratracheal administration of RL and demonstrated anti-inflammatory effects in asthma models. Worse T-helper cell type 2 (Th2)-related inflammatory and pro-inflammatory responses were observed after simultaneous challenge with ovalbumin (OVA) and WPM. To establish a model of asthma exacerbated by WPM, BALB/c mice were sensitized with OVA + aluminum hydroxide and challenged with OVA + WPM. To confirm the therapeutic efficacy of RL, it was administered both orally and intratracheally. Histopathological analysis of H&E staining confirmed that oral and intratracheal administration of RL alleviated inflammatory cell infiltration in the airways aggravated by OVA + WPM. RL effectively reduced the number of inflammatory cells obtained from the bronchoalveolar lavage fluid. In addition, enzyme-linked immunosorbent assay (ELISA) and multiplex analysis of serum samples confirmed that the administration of RL reduced the levels of immuno-globulin E (IgE), Th2-related cytokines, and pro-inflammatory cytokines. Furthermore, real-time PCR analysis of lung tissue samples confirmed that the release of MUC5AC (Mucin 5AC, Oligomeric Mucus/Gel-Forming) and pro-inflammatory cytokines was reduced by RL, and western blotting confirmed that the administration of RL reduced the phosphorylation of ERK and p38 in the MAPK pathway. In conclusion, oral and intratracheal administration of RL appears to have an anti-asthmatic effect by reducing the secretion of Th2-related cytokines, pro-inflammatory cytokines, and IgE by downregulating the MAPK pathway. Thus, RL has further demonstrated potential for development as an oral and inhaled therapeutic for asthma symptoms exacerbated by WPM exposure.
PubMed: 35837279
DOI: 10.3389/fphar.2022.925502 -
Northern Clinics of Istanbul 2022Intratracheal (IT) and intravenous (IV) lignocaine suppress airway reflex and hemodynamic response during extubation, but studies regarding this are sparse. The primary...
A randomized controlled trial to study the effect of intratracheal and intravenous lignocaine on airway and hemodynamic response during emergence and extubation following general anesthesia.
OBJECTIVE
Intratracheal (IT) and intravenous (IV) lignocaine suppress airway reflex and hemodynamic response during extubation, but studies regarding this are sparse. The primary aim was to compare the effect of IT and IV lignocaine on attenuation of airway reflex to endotracheal extubation and the secondary aim was to compare the hemodynamic responses to extubation, using lignocaine by the two different routes.
METHODS
Seventy-five female patients with comparable age, body mass index, and American Society of Anesthesiologists Physical Status undergoing carcinoma breast surgery were randomized into three groups. Group A received 2% lignocaine 3 mg/kg intratracheally 5 min and Group B received 2% lignocaine 1.5 mg/kg intravenously 3 min before extubation. Group C was control group. The airway and hemodynamic responses were noted in terms of episodes of cough during emergence and extubation. Categorical variables assessed using Fisher's exact test and continuous variables assessed using one-way analysis of variance.
RESULTS
Cough suppression was present in Groups A and B, with better results observed with IT than with IV lignocaine. In the control group, Grade III cough reflex was present predominantly. There was a statistically significant difference (p<0.001) in blood pressure and heart rate between Group A versus Group C and in Group B versus Group C, but not between Group A and Group B.
CONCLUSION
IT lignocaine administered before extubation significantly attenuates post-extubation cough reflex than IV lignocaine. Both IT and IV lignocaine can effectively attenuate the airway and hemodynamic response to extubation.
PubMed: 36276564
DOI: 10.14744/nci.2021.33407 -
Scientific Reports Jul 2022Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the...
Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecFCD11cCD11b AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.
Topics: Animals; Anti-Asthmatic Agents; Asthma; Female; Immunity, Innate; Inflammation; Lung; Lymphocytes; Macrophages; Mesenchymal Stem Cells; Mice
PubMed: 35821386
DOI: 10.1038/s41598-022-14846-y -
Trials Nov 2023Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is... (Randomized Controlled Trial)
Randomized Controlled Trial
Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.
BACKGROUND
Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation.
METHODS
An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity).
STATISTICAL ANALYSIS PLAN
A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.
Topics: Humans; Infant, Newborn; Bronchopulmonary Dysplasia; Budesonide; Infant, Extremely Premature; Pulmonary Surfactants; Surface-Active Agents
PubMed: 37932774
DOI: 10.1186/s13063-023-07650-0 -
PloS One 2023Chronic obstructive pulmonary disease (COPD) causes sarcopenia and osteoporosis. However, the mechanisms underlying muscle and bone loss as well as the interactions...
Chronic obstructive pulmonary disease (COPD) causes sarcopenia and osteoporosis. However, the mechanisms underlying muscle and bone loss as well as the interactions between muscle and bone in the COPD state remain unclear. Therefore, we herein investigated the effects of the COPD state on muscle and bone in mice intratracheally administered porcine pancreatic elastase (PPE). The intratracheal administration of PPE to mice significantly reduced trabecular bone mineral density (BMD), trabecular bone volume, trabecular number, cortical BMD and cortical area. It also significantly decreased grip strength, but did not affect muscle mass or the expression of myogenic differentiation-, protein degradation- or autophagy-related genes in the soleus and gastrocnemius muscles. Among the myokines examined, myostatin mRNA levels in the soleus muscles were significantly elevated in mice treated with PPE, and negatively related to grip strength, but not bone parameters, in mice treated with or without 2 U PPE in simple regression analyses. Grip strength positively related to bone parameters in mice treated with or without PPE. In conclusion, we showed that a PPE model of COPD in mice exerts dominant effects on bone rather than skeletal muscles. Increased myostatin expression in the soleus muscles of mice in the COPD state may negatively relate to a reduction in grip strength, but not bone loss.
Topics: Mice; Swine; Animals; Myostatin; Pancreatic Elastase; Pulmonary Emphysema; Pulmonary Disease, Chronic Obstructive; Emphysema; Bone Density; Muscle, Skeletal; Bone Diseases, Metabolic
PubMed: 37352205
DOI: 10.1371/journal.pone.0287541 -
Inflammation Research : Official... Jan 2023Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI)...
BACKGROUND
Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression.
METHODS
Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100β and pan leukocyte marker CD45.
RESULTS
Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100β, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus.
CONCLUSIONS
Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.
Topics: Animals; Female; Mice; Claudin-4; Cross-Sectional Studies; Epithelial Cell Adhesion Molecule; Inflammation; Lipopolysaccharides; Lung; Pneumonia; Ileum
PubMed: 36322182
DOI: 10.1007/s00011-022-01657-0 -
Trials May 2023Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is...
Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial.
BACKGROUND
Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD.
METHODS
An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity).
DISCUSSION
Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017.
Topics: Child, Preschool; Infant, Newborn; Infant; Humans; Surface-Active Agents; Budesonide; Bronchopulmonary Dysplasia; Infant, Extremely Premature; Australia; Pulmonary Surfactants; Drug-Related Side Effects and Adverse Reactions; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37161488
DOI: 10.1186/s13063-023-07257-5 -
Veterinary Pathology Jul 2022Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an ongoing pandemic with millions of deaths...
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an ongoing pandemic with millions of deaths worldwide. Infection of humans can be asymptomatic or result in fever, fatigue, dry cough, dyspnea, and acute respiratory distress syndrome with multiorgan failure in severe cases. The pathogenesis of COVID-19 is not fully understood, and various models employing different species are currently applied. Ferrets can be infected with SARS-CoV-2 and efficiently transmit the virus to contact animals. In contrast to hamsters, ferrets usually show mild disease and viral replication restricted to the upper airways. Most reports have used the intranasal inoculation route, while the intratracheal infection model is not well characterized. Herein, we present clinical, virological, and pathological data from young ferrets intratracheally inoculated with SARS-CoV-2. Infected animals showed no significant clinical signs, and had transient infection with peak viral RNA loads at 4 days postinfection, mild to moderate rhinitis, and pulmonary endothelialitis/vasculitis. Viral antigen was exclusively found in the respiratory epithelium of the nasal cavity, indicating a particular tropism for cells in this location. Viral antigen was associated with epithelial damage and influx of inflammatory cells, including activated neutrophils releasing neutrophil extracellular traps. Scanning electron microscopy of the nasal respiratory mucosa revealed loss of cilia, shedding, and rupture of epithelial cells. The currently established ferret SARS-CoV-2 infection models are comparatively discussed with SARS-CoV-2 pathogenesis in mink, and the advantages and disadvantages of both species as research models for zoonotic betacoronaviruses are highlighted.
Topics: Animals; Antigens, Viral; COVID-19; Cricetinae; Disease Models, Animal; Ferrets; Respiratory Mucosa; SARS-CoV-2
PubMed: 35001763
DOI: 10.1177/03009858211071012