Changes In Lung Weight Research Articles

Effects of Paracetamol, Amoxicillin, and their Combination on Male Rabbit Body and Organs Weight

The administration of pharmaceuticals such as paracetamol (PAR) and amoxicillin (AMO) has been linked to physiological changes in animals. While these drugs are widely utilized for their therapeutic benefits, their potential effects on body and organ weights are not fully understood. Male rabbits were divided into four groups a control group, a group treated with PAR, a group treated with AMO, and a group receiving both drugs PAR+AMO. Body weight changes were monitored weekly, and organ weights (liver, lungs, heart, kidneys, testes, and brain) were measured at the end of the trial. Data were statistically analyzed, with significance set at p < 0.05. Body weight changes were observed across all treatment groups. In the control group, there were gradual weight increase from 1839±136.20g to 1975±89.94g, remaining consistent throughout the trial. While in the PAR group, we observed initial weight loss from 1667±43.83g to 1584±31.69g in week one, followed by recovery and reaching 1860±26.48g by week five. In the AMO group, there were a minor initial weight loss, followed by steady gains peaking at 2028±12.02g in week four, slightly decreasing to 2007±4.97g in week five. In the PAR+AMO group, we reported fluctuations in weight, starting at 1857±52.43g, peaking in week one (2001±94.50g), and ending at 1900±92.61g in week five. Organ weight analysis revealed significant changes. Liver and Lungs were notable increases in the PAR (73.214±5.006g liver; 8.356±0.663g lungs) and AMO groups (76.250±0.364g liver; 6.650±0.030g lungs). Combination therapy moderated these effects. Other Organs such as kidney, heart, brain, and testes weights showed no significant alterations (p > 0.05) across the groups. In conclusion, this study highlights the differential impact of PAR and AMO, individually and in combination, on body and organ weights in male rabbits. While PAR and AMO caused notable changes in liver and lung weights, combination therapy appeared to moderate these effects. Body weight fluctuations were observed across all groups, emphasizing the need for further investigation into the mechanisms underlying these physiological responses to pharmaceutical interventions.

Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition characterized by widespread inflammation and pulmonary edema. Adrenomedullin (AM), a bioactive peptide with various functions, is expected to be applied in treating ARDS. Its functions are regulated primarily by two receptor activity-modifying proteins, RAMP2 and RAMP3, which bind to the AM receptor calcitonin receptor-like receptor (CLR). However, the roles of RAMP2 and RAMP3 in ARDS remain unclear. We generated a mouse model of ARDS via intratracheal administration of lipopolysaccharide (LPS), and analyzed the pathophysiological significance of RAMP2 and RAMP3. RAMP2 expression declined with LPS administration, whereas RAMP3 expression increased at low doses and decreased at high doses of LPS. After LPS administration, drug-inducible vascular endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2−/−) showed reduced survival, increased lung weight, and had more apoptotic cells in the lungs. DI-E-RAMP2−/− mice exhibited reduced expression of Epac1 (which regulates vascular endothelial cell barrier function), while RAMP3 was upregulated in compensation. In contrast, after LPS administration, RAMP3−/− mice showed no significant changes in survival, lung weight, or lung pathology, although they exhibited significant downregulation of iNOS, TNF-α, and NLRP3 during the later stages of inflammation. Based on transcriptomic analysis, RAMP2 contributed more to the circulation-regulating effects of AM, whereas RAMP3 contributed more to its inflammation-regulating effects. These findings indicate that, while both RAMP2 and RAMP3 participate in ARDS pathogenesis, their functions differ distinctly. Further elucidation of the pathophysiological significance and functional differences between RAMP2 and RAMP3 is critical for the future therapeutic application of AM in ARDS.

Role of hyperglycemia in cystic fibrosis pulmonary exacerbations

BackgroundHyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations. MethodsThe STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables. ResultsGlucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL. ConclusionsHyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations.

Nicotinamide Mononucleotide Ameliorates Silica-Induced Lung Injury through the Nrf2-Regulated Glutathione Metabolism Pathway in Mice

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2. Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

Time course of pulmonary inflammation and trace element biodistribution during and after sub-acute inhalation exposure to copper oxide nanoparticles in a murine model

BackgroundIt has been shown that copper oxide nanoparticles (CuO NPs) induce pulmonary toxicity after acute or sub-acute inhalation exposures. However, little is known about the biodistribution and elimination kinetics of inhaled CuO NPs from the respiratory tract. The purposes of this study were to observe the kinetics of pulmonary inflammation during and after CuO NP sub-acute inhalation exposure and to investigate copper (Cu) biodistribution and clearance rate from the exposure site and homeostasis of selected trace elements in secondary organs of BALB/c mice.ResultsSub-acute inhalation exposure to CuO NPs led to pulmonary inflammation represented by increases in lactate dehydrogenase, total cell counts, neutrophils, macrophages, inflammatory cytokines, iron levels in bronchoalveolar lavage (BAL) fluid, and lung weight changes. Dosimetry analysis in lung tissues and BAL fluid showed Cu concentration increased steadily during exposure and gradually declined after exposure. Cu elimination from the lung showed first-order kinetics with a half-life of 6.5 days. Total Cu levels were significantly increased in whole blood and heart indicating that inhaled Cu could be translocated into the bloodstream and heart tissue, and potentially have adverse effects on the kidneys and spleen as there were significant changes in the weights of these organs; increase in the kidneys and decrease in the spleen. Furthermore, concentrations of selenium in kidneys and iron in spleen were decreased, pointing to disruption of trace element homeostasis.ConclusionsSub-acute inhalation exposure of CuO NPs induced pulmonary inflammation, which was correlated to Cu concentrations in the lungs and started to resolve once exposure ended. Dosimetry analysis showed that Cu in the lungs was translocated into the bloodstream and heart tissue. Secondary organs affected by CuO NPs exposure were kidneys and spleen as they showed the disruption of trace element homeostasis and organ weight changes.

A new and simple parameter for diagnosis pulmonary edema: Expiratory air humidity

PurposeAcute pulmonary edema is characterized by increased levels of fluid in the interstitial and alveolar space of the lung and requires emergency treatment. In acute pulmonary edema, the amount of fluid in the intra-alveolar, interstitial space, and pleural space vary considerably and this fluid will evaporate in different amounts compared to the physiological fluid. The aim of this study was to compare the humidity rates of expiratory air measured before and after pulmonary edema induced by α-naphthylthiourea (ANTU) in rats. MethodsThe study included twenty healthy adult rats divided equally into a healthy control group and a pulmonary edema group. Pulmonary edema was induced by administering ANTU intraperitoneally in the rats in the study group. Humidity, temperature, lung weight, pleural effusion, and histopathological changes in the respiratory system due to pulmonary edema were examined in the ANTU group. Control measurments were taken before administration of ANTU and again 4 h after administration of ANTU when lung damage was considred to be at maximum levels. ResultsMean expiratory air humidity was 71.22±3.59% before ANTU and 56.28±3.94% after administration of ANTU. The mean humidity difference of -14.94±5.96% was considered statistically different (p = 0.01). ConclusionHumidity rate in expiratory air was significantly lower in rats with acute pulmonary edema compared to healthy rats. This result supports the hypothesis that humidity in expiratory air can be considered an important parameter in patients during clinical are follow-up for pulmonary edema.

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Real-Time Lung Weight Measurement during Ex Vivo Lung Perfusion: Clinical Importance of Early Weight Gain

<h3>Purpose</h3> Lung weight gain during ex vivo lung perfusion (EVLP) can reduce lung transplant suitability. Therefore, real-time weight measurement can enhance donor lung evaluation. We sought to 1) develop/validate a real-time EVLP weight measurement system, and 2) define the time course of lung weight change during EVLP. <h3>Methods</h3> In our clinical acellular EVLP system, from 6/2019-9/2020, real-time lung weight was measured in 36 cases. Weights were recorded with a scale under the organ chamber, and back table static weights measured after EVLP. Lungs were classified as unfavorable (n = 13) if declined after EVLP (n = 8) or PGD grade ≥ 2 at 72 hrs if transplanted (n = 5). Favorable group lungs were transplanted, with PGD ≤ 1 at 72 hrs (n = 23). <h3>Results</h3> Real-time lung weights correlated well with static/back table weights (r = 0.69, p < 0.01, Figure A). Unfavorable group lungs gained significantly more weight (mean 38 g, range -59 to 135 g) during the 1^st hour of EVLP vs. favorable group lungs (mean -51 g, range -155 to +53 g) (p < 0.01, Figure B). In fact, this effect was most pronounced in the first 10 minutes of EVLP (Figure C), and correlated with an increased pulmonary artery (PA) pressures (7.0 ± 2.2 vs 5.4 ± 1.3 mmHg, p = 0.03). In contrast, lung weight gain was similar between groups during EVLP hours 2 and 3. For the 28 lungs suitable for transplant, 30-day recipient survival was 100%. <h3>Conclusion</h3> Real-time lung weight measurement during EVLP is feasible. Our data suggest that donor lung weight gain in the earliest phase of EVLP correlates with decreased lung transplant suitability and PGD. Further studies are needed to define the significance of lung weight gain early during EVLP.

Significance of Lung Weight in Cellular Ex Vivo Lung Perfusion

BackgroundCurrently, pulmonary edema is evaluated via surgical inspection and palpation in donor lungs, and there is no quantitative standard diagnostic tool for evaluating pulmonary edema in donor procurement and ex vivo lung perfusion (EVLP). The purpose of this study was to investigate the significance of lung weight at the donor hospital and lung weight during EVLP as a complementary parameter of transplant suitability in EVLP. Materials and methodsTwenty-one of rejected human lungs were perfused in cellular EVLP. Transplant suitability was evaluated at 2 h as per standard criteria of Lund-protocol EVLP. ResultsLung weight at donor hospital was significantly correlated with PaO2/FiO2 (P/F) ratio in EVLP (r = −0.44). There was a significant difference in lung weight at donor hospital between suitable cases (n = 13) and nonsuitable cases (n = 8). Light lung group (lung weight at donor hospital < 1280 g; n = 17) was suitable for transplant in 76%, whereas none of heavy lung group (lung weight at donor hospital ≥ 1280 g; n = 4) was suitable (P < 0.05). Lung weight at 2 h and lung weight change during EVLP were significantly associated with P/F ratio at 2 h and transplant suitability (P < 0.05, each). ConclusionsOur findings demonstrate that lung weight at donor hospital, lung weight change, and lung weight at 2 h of EVLP might be a predictor of P/F ratio and transplant suitability in cellular EVLP.

Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation.

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.

Real-Time Lung Weight Measurement: A Simple Predictor for Clinical Outcomes of Ex-Vivo Lung Perfusion

Lung weight (LW) gain is a typical characteristic of ischemia reperfusion injury in ex-vivo lung perfusion (EVLP). However, LW gain data is available only at the end of EVLP. Additionally, objective physiological parameters useful in EVLP evaluation are limited. The study purpose was to investigate the usefulness of real-time LW measurement to assess pulmonary edema and to predict clinical outcomes. LW at back table was measured before and after EVLP. During acellular EVLP, real-time LW was continuously measured by a scale attached under the organ chamber. The LW change (weight change per time, g/min) was measured during the non-touching period at multiple time points and the estimated LW gain was calculated by LW change and its duration. Transplant suitability was judged based on the standard criteria including trend of physiological parameters and palpation findings. Ten lungs were perfused at our institute and 8 lungs were clinically transplanted. All patients survived and primary graft dysfunction (PGD) grade at 72 hours were Grade 0-1, n = 6; Grade 2, n = 2; Grade 3, n = 0. Estimated LW gain during the entire perfusion period significantly correlated with LW gain at the back table (n = 10, r = 0.95, p < 0.01, Fig. 1A). Furthermore, initial LW gain (0-60 min) had a significant correlation with back table LW gain, compared with LW gain after 60 min of EVLP (n = 10, r = 0.79, p < 0.01, Fig. 1B). Non-suitable group had significantly higher initial LW gain compared to suitable group (120 ± 30 vs -17 ± 56 g, p = 0.02, Fig. 1C). Unfavorable outcome group (defined as non-suitable or PGD grade 2-3) group had significantly higher initial LW gain compared to favorable outcome group (defined as PGD grade 0-1, 75 ± 56 vs -32 ± 58 g, p = 0.02, Fig. 1D). The data suggest that LW gain calculated by real-time LW measurement might be useful to assess pulmonary edema during EVLP. Initial LW gain at 0-60 min of EVLP might be a predictor of transplant suitability and clinical outcomes.

Factors associated with compensatory lung growth after pulmonary lobectomy for lung malignancy: an analysis of lung weight and lung volume changes based on computed tomography findings.

To establish the factors associated with compensatory lung growth (CLG) in human adults. The subjects of this study were 216 patients who underwent pulmonary lobectomy between January 2008 and March 2015 and had computed tomography (CT) scans done before and 2years after surgery with no signs of recurrence. The predicted postoperative values of lung volume and lung weight, based on the preoperative CT data, were compared with those 2years after surgery. When the predicted postoperative values were considered to be 100%, the mean lung volume and lung weight 2years after surgery were 116 ± 16% and 115 ± 19%, respectively. CLG was defined as both lung volume ≥ 110% and lung weight ≥ 106% (CLG group; n = 108). Both univariate and multivariate analyses showed that younger age (≤ 60years), a larger number of resected subsegments (≥ 10), and a light- (< 20 pack-years) or non-smoking history were significantly associated with CLG. This study identified younger age, a light- or non-smoking history, and a large resection volume as the predictors of CLG in patients who underwent pulmonary lobectomy for lung malignancy. All of these three factors may be reasonably connected to CLG.

Post-infarct morphine treatment mitigates left ventricular remodeling and dysfunction in a rat model of ischemia-reperfusion

Following myocardial infarction, the heart undergoes a series of dramatic compensations which may later form a maladaptive picture characterized by ventricular dilation and pump failure. Among several opioid agents, morphine has been shown to confer protection against reperfusion injury and infarct size. Here, we sought to study the cardioprotective effect of post-infarct morphine treatment against left ventricular adverse remodeling. We induced myocardial infarction in male Sprague - Dawley rats by ligating left anterior descending artery and then, treated these animals with three different doses of morphine −0.3, 3 and 10 mg/kg (i.p.). The echocardiographic evaluation depicted improved cardiac performance and lesser chamber dilation in the animals that had received 3 mg/kg of morphine. Next, we studied the effect of 3 mg/kg morphine administration on left ventricular hemodynamics, infarct size, tissue architecture, changes in lung and heart weight, circulating TNF-α level and post-MI mRNA expression of collagen-1, collagen-3, TGF-β, TNF-α, MMP-2 and MMP-9. Five-day morphine administration markedly improved LV function, and also reduced infarct size, myocyte hypertrophy, fibrosis, index of infarct expansion, heart weight and serum TNF-α level. Moreover, morphine alleviated MI-induced increase in wet and dry lung weight. Morphine also altered the mRNA expression of fibrosis-related genes, TNF-α, MMP-2 and MMP-9. In conclusion, post-infarct morphine treatment can mitigate adverse remodeling and cardiac dysfunction after MI. Beside analgesic effect, we may be able to harvest benefits from the antifibrotic and anti-remodeling action of morphine in patients with the acute coronary syndrome.

Cytochrome P450 1B1 (CYP1B1) Knockout Mice are Less Susceptible to Hyperoxic Pulmonary Injury: A Novel Pro‐Oxidant Role for CYP1B1 in Vivo

Supplemental oxygen is a life‐saving intervention provided to individuals suffering from respiratory distress, including adults with acute respiratory distress syndrome (ARDS) as well as premature newborns with respiratory distress syndrome. However, experimental evidence has shown that supplemental oxygen can create a hyperoxic environment which can lead to and exacerbate existing pulmonary injury due to increases in pathogenic reactive oxygen species (ROS) and oxidative stress. Many molecular and biochemical mechanisms are known to regulate ROS levels and oxidative stress, but previous studies have shown the importance of cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) as well as the aryl hydrocarbon receptor (AHR) in the protection against hyperoxic lung injury. Further, there is evidence suggesting that cytochrome P450 1B1 (CYP1B1) may contribute to hyperoxic toxicity in human epithelial cells. The objective of this study was to test the hypothesis that CYP1B1 mechanistically contributes to hyperoxia‐induced toxicity. Ten‐week‐old C57BL/6 (WT) and Cyp1b1−/− male mice were exposed to hyperoxia (&gt;95% oxygen) for 24–72 hours or maintained in room air as a control group. Lung weight changes were used to quantify lung injury. Mass spectrometry and 32P‐postlabeling were used to quantify lipid peroxidation and oxidative DNA damage, respectively, as markers of oxidative stress. Western blot and qPCR were used to quantify CYP1 protein and RNA expression. We found that Cyp1b1−/− mice had significantly decreased normalized lung weights after 48 (P=0.04) and 72 hours (P=0.017) of hyperoxia exposure, indicating reduced pulmonary edema and lung injury. We also found that Cyp1b1−/− mice have lower pulmonary isofurans (P=0.0331) and oxidative DNA adducts (P=0.0157) after 24 hours of hyperoxia. Gene expression studies showed that Cyp1b1−/− mice had increased CYP1A1 (P=2.9×10‐05) RNA expression during hyperoxia exposure and increased CYP1A2 (P=0.016) RNA expression after 48 hours of hyperoxia. Our results support the hypothesis that CYP1B1 contributes to hyperoxic lung injury, possibly by increasing ROS levels and oxidative stress. Our results also suggest that Cyp1b1−/− mice display lesser lung injury in part via increased transcriptional activation of Cyp1a1/1a2 genes. The goal of future studies will be to determine if CYP1B1 directly contributes to injury by creating a pro‐oxidant environment or indirectly contributes to injury by negatively feeding back on protective AHR‐dependent transcription. Elucidating the mechanism underlying these observations will help determine the viability of CYP1B1‐directed therapeutics and treatment strategies to treat and/or prevent hyperoxia toxicity and improve care for ARDS patients.Support or Funding InformationResearch reported in this publication was supported by the National Institutes of Health under award number R01ES019689, R01ES009132, R01HL12516, R01HL129794, and R01HL087174 to B.M., R01HL088343 to X.I.C., and T32GM088129 to A.C.V. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

High Throughput Combinatorial Formatting of PcrV Nanobodies for Efficient Potency Improvement

Improving potencies through concomitant blockage of multiple epitopes and avid binding by fusing multiple (different) monovalent Nanobody building blocks via linker sequences into one multivalent polypeptide chain is an elegant alternative to affinity maturation. We explored a large and random formatting library of bivalent (combinations of two identical) and biparatopic (combinations of two different) Nanobodies for functional blockade of Pseudomonas aeruginosa PcrV. PcrV is an essential part of the P. aeruginosa type III secretion system (T3SS), and its oligomeric nature allows for multiple complex binding and blocking options. The library screening yielded a large number of promising biparatopic lead candidates, revealing significant (and non-trivial) preferences in terms of Nanobody building block and epitope bin combinations and orientations. Excellent potencies were confirmed upon further characterization in two different P. aeruginosa T3SS-mediated cytotoxicity assays. Three biparatopic Nanobodies were evaluated in a lethal mouse P. aeruginosa challenge pneumonia model, conferring 100% survival upon prophylactic administration and reducing lung P. aeruginosa burden by up to 2 logs. At very low doses, they protected the mice from P. aeruginosa infection-related changes in lung histology, myeloperoxidase production, and lung weight. Importantly, the most potent Nanobody still conferred protection after therapeutic administration up to 24 h post-infection. The concept of screening such formatting libraries for potency improvement is applicable to other targets and biological therapeutic platforms.

The Protective Effects of Gadolinum Chloride on Pneumotoxic Effects of Styrene in Rat.

The aim of the present study was to evaluate the protective effects of gadoli- num on pneumotoxic effects of styrene in rats as an experimental model. In this experimental study a total number of 40 adult male Sprague Dawley rats that weighed 200 ± 13 g were randomly divided into five groups: i. styrene (St, N=10), ii. styrene+gadolinium chloride (GdCl3, N=10), iii. control (N=10), iv. GdCl3 (N=5) and v. normal saline (Nor.Sal, as a solvent of GdCl3, N=5). Normal saline, as a sham control group, was otherwise treated identically. Rats from the experimental groups were exposed to St in an exposure chamber for 6 days/week, 4 hours/day for up to 3 weeks. At the end of the experi- ment, rats from all groups were killed by deep anesthesia. Their lungs were removed, then fixed in formalin and weighed. Tissue samples were processed routinely and sections stained by the hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) methods. We measured the thicknesses of the respiratory epithelia and interalveolar septa. Obtained data were ana- lyzed by ANOVA, the Tukey test and the paired t test. Shedding of apical cytoplasm in the bronchiole was a prominent feature of the St group. PAS staining revealed histochemical changes in goblet cells in the epithelium of the St group. While there were no significant changes in lung weights and respiratory epithelial thicknesses between all studied groups, statistical analysis showed a significant alteration in the thickness of interalveolar septa in the St and St+GdCl3 group compared to the control groups (P<0.001). Styrene induced structural and histochemical changes in bronchiole, interalveolar septa and alveolar organization in the rats' lungs. Gadolinium appeared to partially reduce the toxic effects of styrene on the lungs.

Exposure to Cerium Oxide Nanoparticles Is Associated With Activation of Mitogen-activated Protein Kinases Signaling and Apoptosis in Rat Lungs.

Objectives:With recent advances in nanoparticle manufacturing and applications, potential exposure to nanoparticles in various settings is becoming increasing likely. No investigation has yet been performed to assess whether respiratory tract exposure to cerium oxide (CeO2) nanoparticles is associated with alterations in protein signaling, inflammation, and apoptosis in rat lungs.Methods:Specific-pathogen-free male Sprague-Dawley rats were instilled with either vehicle (saline) or CeO2 nanoparticles at a dosage of 7.0 mg/kg and euthanized 1, 3, 14, 28, 56, or 90 days after exposure. Lung tissues were collected and evaluated for the expression of proteins associated with inflammation and cellular apoptosis.Results:No change in lung weight was detected over the course of the study; however, cerium accumulation in the lungs, gross histological changes, an increased Bax to Bcl-2 ratio, elevated cleaved caspase-3 protein levels, increased phosphorylation of p38 MAPK, and diminished phosphorylation of ERK-1/2-MAPK were detected after CeO2 instillation (p<0.05).Conclusions:Taken together, these data suggest that high-dose respiratory exposure to CeO2 nanoparticles is associated with lung inflammation, the activation of signaling protein kinases, and cellular apoptosis, which may be indicative of a long-term localized inflammatory response.

Indoline-3-propionate and 3-aminopropyl carbamates reduce lung injury and pro-inflammatory cytokines induced in mice by LPS.

In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression.

Spillover of cytokines and reactive oxygen species in ventilator-induced lung injury associated with inflammation and apoptosis in distal organs.

The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. VILI was induced in rat lungs with high tidal volume (V(T)) ventilation of 40 mL/kg for 6 h. Rats with low V(T) ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H2O2, interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H2O2, IL-1β, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H2O2, IL-1β, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. High V(T) ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

An integrated physiology model to study regional lung damage effects and the physiologic response.

BackgroundThis work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement.MethodsA pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement.ResultsThe augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage.ConclusionsWe have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations.