Pharmacokinetic/Pharmacodynamic Modeling of Total Lymphocytes and Selected Subtypes After Oral Budesonide

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3 mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9 mg), and five received three capsules of Dosage Form B (single dose of 9 mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC₅₀ value for unbound BUD acting on total lymphocytes was 0.276 ng/ml while the IC₅₀ values for unbound BUD acting on lymphocyte subtypes ranged from 0.150 ng/ml for CD4 to 0.364 ng/ml for CD8. The IC₅₀ values for the effects of BUD on serum cortisol were lower (0.079 ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.     

Hesperidin ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting HMGB1 release

Hesperidin (HDN), a flavanone glycoside, possesses anti-inflammatory properties and has been suggested to be able to modulate the lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1) serves as an inflammatory cytokine when released extracellularly and is involved in the pathogenesis of diverse inflammatory disorders. The current study aimed to investigate the involvement of HMGB1 in HDN-induced immunoregulation of ALI. ALI in male BALB/c mice was induced by intranasal administration of LPS (0.5 mg/kg). HDN (500 mg/kg) was administered intragastrically 10 days prior to LPS exposure. HDN significantly protected animals from LPS-induced ALI as evidenced by decreased elevation of the lung wet to dry weight ratio, total cells, neutrophils, macrophages, and myeloperoxidase (MPO) activity, associated with reduced lung histological damage. In the meantime, HDN pretreatment markedly inhibited the production of pro-inflammatory cytokines and chemokine, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Furthermore, HDN pretreatment dramatically inhibited the infiltration of macrophages and suppressed the expression and release of HMGB1 in vivo and in vitro. In addition, intranasal application of exogenous HMGB1 could result in lung injury which was also alleviated by HDN administration. These results suggest that HDN pretreatment protects mice from LPS-induced ALI via inhibiting the production of TNF-α and IL-6. Moreover, we found that HDN could inhibit the expression and release of HMGB1 via suppressing the infiltration of macrophages and production of MCP-1.     

Green synthesis of gold nanoparticles modulates lipopolysaccharide-induced lung inflammation in Wistar rats

This study aimed to investigate the effect of intranasal treatment of gold nanoparticles (GNPs) and Curcumin (Cur) on the lipopolysaccharide (LPS)-induced acute pulmonary inflammatory response. A single intraperitoneal injection of LPS (0.5 mg/Kg) was performed, and the animals in the Sham group were injected with 0.9% saline. Treatment was daily intranasally with GNPs (2.5 mg/L), Cur (10 mg/kg) and GNP-Cur started 12 h after LPS administration and ended on the seventh day. The results show that the treatment performed with GNP-Cur was the most effective to attenuate the action of pro-inflammatory cytokines, and a lower leukocyte count in the bronchoalveolar lavage, in addition to positively regulating anti-inflammatory cytokines in relation to other groups. As a result, it promoted an oxirreductive balanced environment in the lung tissue, providing a histological outcome with a reduction in inflammatory cells and greater alveolar area. The group treated with GNPs-Cur was superior to the other groups, with better anti-inflammatory activity and reduced oxidative stress, resulting in less morphological damage to lung tissue. In conclusion, the use of reduced GNPs with curcumin demonstrates promising effects in the control of the acute inflammatory response, helping to protect the lung tissue at the biochemical and morphological levels.     

Harnessing of Doxylamine Succinate/Pyridoxine Hydrochloride-Dual Laden Bilosomes as a Novel Combinatorial Nanoparadigm for Intranasal Delivery: In Vitro Optimization and In Vivo Pharmacokinetic Appraisal

The present work is concerned with tailoring and appraisal of a novel nano-cargo; bilosomes (BLS) dual laded with doxylamine succinate (DAS) and pyridoxine hydrochloride (PDH), the first treatment option against gestational nausea and vomiting, for intranasal delivery. This bifunctional horizon could surmount constraints of orally-commercialized platforms both in dosage regimen and pharmacokinetic profile. For accomplishing this purpose, DAS/PDH-BLS were elaborated integrating phospholipid, sodium cholate and cholesterol applying thin-film hydration method based on Box-Behnken design. Utilizing Design-Expert® software, the effect of formulation variables on BLS physicochemical features alongside the optimal formulation selection were investigated. Then, the optimum DAS/PDH-BLS formulation was incorporated into a thermally-triggered in situ gelling base. The in vivo pharmacokinetic studies were explored in rats for intranasal DAS/PDH-BLS in situ gel compared with analogous intranasal free in situ gel and oral solution. The optimized BLS disclosed vesicle size of 243.23 nm, ζ potential of -31.33 mV, entrapment efficiency of 59.18 and 41.63%, accumulative % release within 8 h of 63.30 and 85.52% and accumulative permeated amount over 24 h of 347.92 and 195.4 µg/cm² for DAS/PDH, respectively. Following intranasal administration of the inspected BLS in situ gel, pharmacokinetic studies revealed a 1.64- and 2.3-fold increment in the relative bioavailability of DAS and a 1.7- and 3.73-fold increase for PDH compared to the intranasal free in situ gel and oral solution, respectively besides significantly extended mean residence times for both drugs. Thus, the intranasally exploited DAS/PDH-BLS could be deemed as a promising hybrid nanoplatform with fruitful pharmacokinetics and tolerability traits.     

Effects of 15-deoxy-Delta12,14-prostaglandin J2 on the expression of Toll-like receptor 4 and 2 in the murine lung in the presence of lipopolysaccharide

1. Previously, we have demonstrated that 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) enhances acute lung injury induced by lipopolysaccharide (LPS) in mice. The enhancement in acute lung injury by 15d-PGJ2 was concomitant with the enhanced expression of several pro-inflammatory cytokines in the lung. However, other underlying mechanisms of this enhancement remain to be elucidated. The present study investigated the effects of 15d-PGJ2 on the expression of Toll-like receptor (TLR) 4 and 2 in the lung in the absence or presence of LPS. 2. In the present study, ICR mice were divided into four experimental groups that received (intratracheally) vehicle, LPS (125 microg/kg), 15d-PGJ2 (1 mg/kg) or 15d-PGJ2 + LPS. The mRNA expression of both TLR4 and 2 in the lung was evaluated 4 h after intratracheal administration. 3. 15-Deoxy-Delta12,14-prostaglandin J2 enhanced the mRNA expression of both TLR4 and 2 in the presence of LPS. 4. These results suggest that the enhancing effects of 15d-PGJ2 on LPS-induced acute lung injury may be explained, at least in part, by its effect on the lung expression of TLR4 and 2.     

Cloning,pharmacological characterization,and polymorphism screening of the guinea pig beta(2)-adrenoceptor

Beside its physiological function as a powerful host defense, neutrophil elastase is also known as one of the most destructive enzymes in the body. Current notion holds that neutrophil elastase is able to escape from regulation by multiple protease inhibitors at inflammatory sites. Once unregulated, this enzyme disturbs the function of the lung permeability barrier and induces the release of pro-inflammatory cytokines. These actions then cause symptoms that are typical in the pathophysiology of acute lung injury. In this article, we review recent progress in the understanding of the physiological activity of neutrophil elastase and its role in acute lung injury. Evidence in this review that supports the involvement of neutrophil elastase in the pathophysiology of acute lung injury includes: (1) neutrophil elastase levels are increased in both clinical and animal models of acute lung injury; (2) topical or systemic administration of neutrophil elastase produces typical symptoms of acute lung injury both in vitro and in vivo; and (3) inhibition of increased neutrophil elastase activity reduces symptoms of acute lung injury in animal models. A greater understanding of the role of this enzyme in the pathophysiology of acute lung injury will lead to better treatments for this complicated disease.     

Corticosteroids found ineffective for phosgene-induced acute lung injury in rats

Various therapeutic regimes have been proposed with limited success for treatment of phosgene-induced acute lung injury (P-ALI). Corticoids were shown to be efficacious against chlorine-induced lung injury but there is still controversy whether this applies also to P-ALI. This study investigates whether different regimen of curatively administered budesonide (BUD, 10 mg/kg bw, i.p. bid; 100 mg/m³ × 30 min, nose-only inhalation), mometasone (MOM, 3 mg/kg bw, i.p. bid) and dexamethasone (DEX, 10, 30 mg/kg bw, i.p. bid), show efficacy to alleviate P-ALI. Efficacy of drugs was judged by nitric oxide (eNO) and carbon dioxide (eCO₂) in exhaled air and whether these non-invasive biomarkers are suitable to assess the degree of airway injury (chlorine) relative to alveolar injury (phosgene). P-ALI related analyses included lung function (enhanced pause, Penh), morbidity, increased lung weights, and protein in bronchial alveolar lavage fluid (BALF) one day postexposure. One of the pathophysiological hallmarks of P-ALI was indicated by increased Penh lasting for approximately 20 h postexposure. Following the administration of BUD, this increase could be suppressed; however, without significant improvement in survival and lung edema (increased lung weights and BALF-protein). Collectively, protocols shown to be efficacious for chlorine (Chen et al., 2013) were ineffective and even increased adversity in the P-ALI model. This outcome warrants further study to seek for early biomarkers suitable to differentiate chlorine- and phosgene-induced acute lung injury at yet asymptomatic stage. The patterns of eNO and eCO₂ observed following exposure to chlorine and phosgene may be suitable to guide the specialized clinical interventions required for each type of ALI.     

Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats

1. In the present study, we investigated the effects of the inducible nitric oxide (iNOS) inhibitors S-methylisothiourea (SMT) and l-N(6)-(1-iminoethyl)-lysine (l-Nil) on endotoxin-induced acute lung injury (ALI), as well as the associated physiological, biomedical and pathological changes, in anaesthetized Sprague-Dawley rats and in rat isolated perfused lungs. 2. Endotoxaemia was induced by an intravenous (i.v.) infusion of lipopolysaccharide (LPS; Escherichia coli 10 mg/kg). Lipopolysaccharide produced systemic hypotension and tachycardia. It also increased the lung weight/bodyweight ratio, lung weight gain, exhaled nitric oxide (NO), the protein concentration in bronchoalveolar lavage and microvascular permeability. 3. Following infusion of LPS, plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-1beta) were markedly elevated. Pathological examination revealed severe pulmonary oedema and inflammatory cell infiltration. Pretreatment with SMT (3 mg/kg, i.v.) or l-Nil (3 mg/kg, i.v.) significantly attenuated the LPS-induced changes and ALI. 4. The results suggest that the inflammatory responses and ALI following infusion of LPS are due to the production of NO, free radicals and pro-inflammatory cytokines through the iNOS system. Inhibition of iNOS is effective in mitigating the endotoxaemic changes and lung pathology. Inhibitors of iNOS may be potential therapeutic agents for clinical application in patients with acute respiratory distress syndrome.     

Antisense oligonucleotide knockdown of mGlu₅ receptor attenuates the antinociceptive tolerance and up-regulated expression of spinal protein kinase C associated with chronic morphine treatment

Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.     

Protective effects of intranasal curcumin on paraquot induced acute lung injury (ALI) in mice

Paraquot (PQ) is widely and commonly used as herbicide and has been reported to be hazardous as it causes lung injury. However, molecular mechanism underlying lung toxicity caused by PQ has not been elucidated. Curcumin, a known anti-inflammatory molecule derived from rhizomes of Curcuma longa has variety of pharmacological activities including free-radical scavenging properties but the protective effects of curcumin on PQ-induced acute lung injury (ALI) have not been studied. In this study, we aimed to study the effects of curcumin on ALI caused by PQ in male parke's strain mice which were challenged acutely by PQ (50 mg/kg, i.p.) with or without curcumin an hour before (5 mg/kg, i.n.) PQ intoxication. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for pathological and biochemical analysis after 48 h of PQ exposure. Curcumin administration has significantly enhanced superoxide dismutase (SOD) and catalase activities. Lung wet/dry weight ratio, malondialdehyde (MDA) and lactate dehydrogenase (LDH) content, total cell number and myeloperoxidase (MPO) levels in BALF as well as neutrophil infiltration were attenuated by curcumin. Pathological studies also revealed that intranasal curcumin alleviate PQ-induced pulmonary damage and pro-inflammatory cytokine levels like tumor necrosis factor-α (TNF-α) and nitric oxide (NO). These results suggest that intranasal curcumin may directly target lungs and curcumin inhalers may prove to be effective in PQ-induced ALI treatment in near future.     

Ghrelin ameliorates bleomycin-induced acute lung injury by protecting alveolar epithelial cells and suppressing lung inflammation

Acute lung injury is a critical illness syndrome consisting of acute respiratory failure with bilateral pulmonary infiltrates that is refractory to current therapies. Acute lung injury is characterized by injury of the alveolar capillary barrier, neutrophil accumulation, and induction of pro-inflammatory cytokines followed by devastating lung fibrosis. Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation, and promotes cell survival. We investigated the pharmacological potential of ghrelin in the treatment of acute lung injury by using a bleomycin-induced acute lung injury model in mice. Ghrelin or saline was given to mice daily starting 1 day after bleomycin administration. Ghrelin-treated mice showed a definitively higher survival rate than saline-treated ones. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of pro-inflammatory cytokines, and subsequent lung fibrosis were notable in ghrelin-treated mice. Additionally, ghrelin administration reduced the injury-induced apoptosis of alveolar epithelial cells. Our results indicate that ghrelin administration exerts a protective effect against acute lung injury by protecting the alveolar epithelial cells and regulating lung inflammation, and highlight ghrelin as a promising therapeutic agent for the management of this intractable disease.     

Suppression of P2X7/NF-κB pathways by Schisandrin B contributes to attenuation of lipopolysaccharide-induced inflammatory responses in acute lung injury

The aim of the present study was to assess the effects and mechanisms of Schisandrin B (SchB) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by intratracheal instillation of LPS (1 mg/kg), and SchB (25, 50, and 75 mg/kg) was injected 1 h before LPS challenge by gavage. After 12 h, bronchoalveolar lavage fluid (BALF) samples and lung tissues were collected. Histological studies demonstrated that SchB attenuated LPS-induced interstitial edema, hemorrhage, and infiltration of neutrophils in the lung tissue. SchB pretreatment at doses of 25, 50, and 75 mg/kg was shown to reduce LPS-induced lung wet-to-dry weight ratio and lung myeloperoxidase activity. In addition, pretreatment with SchB lowered the number of inflammatory cells and pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 in BALF. The mRNA and protein expression levels of nuclear factor kappa B (NF-κB) signaling-related molecules activated by P2X7 were investigated to determine the molecular mechanism of SchB. The findings presented here suggest that the protective mechanism of SchB may be attributed partly to the decreased production of pro-inflammatory cytokines through the inhibition of P2X7/NF-κB activation.     

Protective Effect of Phosphatidylcholine on Lipopolysaccharide-Induced Acute Inflammation in Multiple Organ Injury

Soybean polyunsaturated phosphatidylcholine (PC) is thought to exert anti-inflammatory activities and has potent effects in attenuating acute renal failure and liver dysfunction. The aim of this study was to investigate the effects of PC in protecting multiple organ injury (MOI) from lipopolysaccharide (LPS). Six groups of rats (N=8) were used in this study. Three groups acted as controls and received only saline, hydrocortisone (HC, 6 mg/kg, i.v.) or PC (600 mg/kg, i.p.) without LPS (15 mg/kg, i.p.) injections. Other 3 groups, as the test groups, were administered saline, HC or PC in the presence of LPS. Six hours after the LPS injection, blood and organs (lung, liver and kidney) were collected from each group to measure inflammatory cytokines and perform histopathology and myeloperoxidase (MPO) assessment. Serum cytokines (TNF-α, IL-6 and IL-10) and MPO activities were significantly increased, and significant histopathological changes in the organs were observed by LPS challenge. These findings were significantly attenuated by PC or HC. The treatment with PC or HC resulted in a significant attenuation on the increase in serum levels of TNF-α and IL-6, pro-inflammatory cytokines, while neither PC nor HC significantly attenuated serum levels of IL-10, anti-inflammatory cytokine. In the organs, the enhanced infiltration of neutrophils and expression of ED2 positive macrophage were attenuated by PC or HC. Inductions of MPO activity were also significantly attenuated by PC or HC. From the findings, we suggest that PC may be a functional material for its use as an anti-inflammatory agent.     

Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents

Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.     

Intranasal vaccines for SARS-CoV-2: From challenges to potential in COVID-19 management

Unlike conventional Coronavirus 2019 (COVID-19) vaccines, intranasal vaccines display a superior advantage because the nasal mucosa is often the initial site of infection. Preclinical and clinical studies concerning intranasal immunization elicit high neutralizing antibody generation and mucosal IgA and T cell responses that avoid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in both; the upper and lower respiratory tract. A nasal formulation is non-invasive with high appeal to patients. Intranasal vaccines enable self-administration and can be designed to survive at ambient temperatures, thereby simplifying logistical aspects of transport and storage. In this review, we provide an overview of nasal vaccines with a focus on formulation development as well as ongoing preclinical and clinical studies for SARS-CoV-2 intranasal vaccine products.     

Iron supplementation at high altitudes induces inflammation and oxidative injury to lung tissues in rats

Exposure to high altitudes is associated with hypoxia and increased vulnerability to oxidative stress. Polycythemia (increased number of circulating erythrocytes) develops to compensate the high altitude associated hypoxia. Iron supplementation is, thus, recommended to meet the demand for the physiological polycythemia. Iron is a major player in redox reactions and may exacerbate the high altitudes-associated oxidative stress. The aim of this study was to explore the potential iron-induced oxidative lung tissue injury in rats at high altitudes (6000 ft above the sea level). Iron supplementation (2 mg elemental iron/kg, once daily for 15 days) induced histopathological changes to lung tissues that include severe congestion, dilatation of the blood vessels, emphysema in the air alveoli, and peribronchial inflammatory cell infiltration. The levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), lipid peroxidation product and protein carbonyl content in lung tissues were significantly elevated. Moreover, the levels of reduced glutathione and total antioxidant capacity were significantly reduced. Co-administration of trolox, a water soluble vitamin E analog (25 mg/kg, once daily for the last 7 days of iron supplementation), alleviated the lung histological impairments, significantly decreased the pro-inflammatory cytokines, and restored the oxidative stress markers. Together, our findings indicate that iron supplementation at high altitudes induces lung tissue injury in rats. This injury could be mediated through excessive production of reactive oxygen species and induction of inflammatory responses. The study highlights the tissue injury induced by iron supplementation at high altitudes and suggests the co-administration of antioxidants such as trolox as protective measures.     

The effect of magnolol on the Toll-like receptor 4/nuclear factor kappa B signaling pathway in lipopolysaccharide-induced acute lung injury in mice

Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis has been reported to have anti-inflammatory properties. The purpose of this study was to evaluate the effect of magnolol on acute lung injury induced by lipopolysaccharide in mice. Male BALB/c mice were pretreated with dexamethasone or magnolol 1 h before intranasal instillation of lipopolysaccharide (LPS). 7 h after LPS administration, the myeloperoxidase in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid were determined. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay (ELISA). The extent of phosphorylation of nuclear factor of inhibitory kappa B alpha (IκB-α), nuclear factor kappa-B (NF-κB) p65 and the expression of Toll-like receptor-4 (TLR4) were detected by western blot. The results showed that magnolol markedly attenuated the histological alterations in the lung; reduced the number of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid; decreased the wet/dry weight ratio of lungs in the bronchoalveolar lavage fluid; down-regulated the level of pro-inflammatory mediators, including TNF-α, IL-1β and IL-6; inhibited the phosphorylation of IκB-α, NF-κB p65 and the expression of TLR4, caused by LPS. Taken together, our results suggest that anti-inflammatory effects of magnolol against the LPS-induced acute lung injury may be due to its ability of inhibition TLR4 mediated NF-κB signaling pathways. Magnolol may be a promising potential therapeutic reagent for acute lung injury treatment.     

Effects of carbon black nanoparticles on elastase-induced emphysematous lung injury in mice

Although adverse health effects of particulate matter with a diameter of <100 nm (nanoparticles) have been proposed, biological evidence supporting their promotion of the inflammatory lung response in vivo is limited. This study investigated the impact of pulmonary exposure to carbon black nanoparticles (CBNP) on emphysematous lung injury induced by porcine pancreatic elastase (PPE) in mice. Vehicle, two sizes (14 and 56 nm) of CBNP (50 μg/body: 4 mg/kg), PPE (0.03 U/body: 1 U/kg) or PPE + CBNP was administered intratracheally; thereafter, parameters of inflammatory lung changes were evaluated at several time-points. CBNP of 14 nm significantly induced acute lung inflammation in non-elicited subjects and aggravated PPE-elicited airway neutrophilic inflammation at an early stage (day 1), which was concomitant with the enhanced lung expression of pro-inflammatory cytokines such as interleukin-1β and chemokine such as keratinocyte-derived chemoattractant. Further, 14-nm CBNP exaggerated emphysematous lung structural changes at a delayed stage (day 14). On the other hand, 56-nm CBNP induced lung inflammation but did not influence PPE-elicited pathophysiology in the lung. Taken together, CBNP at an optimal size and dose can exacerbate PPE-induced pulmonary inflammation and emphysema. This enhancement may be mediated, at least partly, via the increased local expression of pro-inflammatory molecules.