Decreased Lung Inflammation Research Articles

Divergent roles of two neuroimmune semaphorins, Sema4A and Sema4D, in regulation of experimental asthma severity (P6041)

Abstract Allergic asthma is characterized by exaggerated Th2 inflammation resulting from interaction between DC and T cells. Molecules acting in this interaction, regulating cell activation and differentiation are desirable therapeutic targets. Based on the previously published data and our results, we hypothesized that neuroimmune semaphorins play critical costimulatory roles in DC - T cell interaction, thereby influencing allergic lung inflammation. To test our hypothesis, we used Sema4A-/- and Sema4D-/- mice in the mouse model of OVA-induced allergic lung response. Our results have shown that both molecules play critical but opposite roles in disease severity. It was significantly potentiated by Sema4A deficiency, what included increased eosinophilic infiltration, AHR, local/systemic IL-13 levels, sera OVA-specific IgG1/ IgG2b/IgE levels, and decreased Treg numbers. Moreover, we defined that Sema4A expression on CD4+ T cells but not on DC was important for Th2 response regulation. In contrast, we found a decrease in lung inflammation and BAL Th2 cytokine levels in allergen-treated Sema4D-/- mice relative to WT mice. In addition, T cell proliferation in OVA323-339 - restimulated Sema4D-/- cell cultures was downregulated suggesting a costimulatory role of Sema4D for T cell activation. However, AHR was not affected by Sema4D deficiency suggesting its negligible role in airway physiology. These data define both molecules as important regulators of Th2-driven lung pathophysiology.

Antigen-specific CD4+ T cell derived IL-10 is uniquely pro-inflammatory in the context of acute influenza (P6234)

Abstract IL-10 is regarded as an anti-inflammatory cytokine which prevents damage from immunopathology with exacerbated immune responses. However, severe lung inflammation in fatal human influenza is accompanied with increased levels of IL-10 as well as other pro-inflammatory cytokines. This information raises questions regarding the role IL-10 plays in inflammation associated with acute influenza. We found that IL-10 was produced by CD4+ T cells in synchronization with pro-inflammatory cytokines during an acute influenza virus infection in mice. IL-10 supplementation during the acute phase increased inflammation leading to death, while IL-10 knockout mice displayed decreased lung inflammation and survival benefits. In the absence of IL-10, influenza-specific CD4+ T cells divided less and produced less pro-inflammatory cytokines despite unaffected Th1 polarity, no increase of regulatory T cell populations, and no alteration in the kinetics of viral eradication. Influenza-specific CD4+ T cell derived IL-10 was more important than IL-10 from other sources for the detrimental effect. In this context of acute influenza in mice, IL-10 also impeded the release of mature TGF-β with decreased neuraminidase-mediated desialylation of host immune cells. The abundance of neuraminidase may contribute to the pro-inflammatory role of IL-10 we demonstrated in this context of acute influenza virus infection.

Effects of Intratracheal Mesenchymal Stromal Cell Therapy during Recovery and Resolution after Ventilator-induced Lung Injury

Mesenchymal stromal cells (MSCs) have been demonstrated to attenuate acute lung injury when delivered by intravenous or intratracheal routes. The authors aimed to determine the efficacy of and mechanism of action of intratracheal MSC therapy and to compare their efficacy in enhancing lung repair after ventilation-induced lung injury with intravenous MSC therapy. : After induction of anesthesia, rats were orotracheally intubated and subjected to ventilation-induced lung injury (respiratory rate 18(-1) min, P insp 35 cm H2O,) to produce severe lung injury. After recovery, animals were randomized to receive: (1) no therapy, n = 4; (2) intratracheal vehicle (phosphate-buffered saline, 300 µl, n = 8); (3) intratracheal fibroblasts (4 × 10 cells, n = 8); (4) intratracheal MSCs (4 × 10(6) cells, n = 8); (5) intratracheal conditioned medium (300 µl, n = 8); or (6) intravenous MSCs (4 × 10(6) cells, n = 4). The extent of recovery after acute lung injury and the inflammatory response was assessed after 48 h. Intratracheal MSC therapy enhanced repair after ventilation-induced lung injury, improving arterial oxygenation (mean ± SD, 146 ± 3.9 vs. 110.8 ± 21.5 mmHg), restoring lung compliance (1.04 ± 0.11 vs. 0.83 ± 0.06 ml · cm H2O(-1)), reducing total lung water, and decreasing lung inflammation and histologic injury compared with control. Intratracheal MSC therapy attenuated alveolar tumor necrosis factor-α (130 ± 43 vs. 488 ± 211 pg · ml(-1)) and interleukin-6 concentrations (138 ± 18 vs. 260 ± 82 pg · ml(-1)). The efficacy of intratracheal MSCs was comparable with intravenous MSC therapy. Intratracheal MSCs seemed to act via a paracine mechanism, with conditioned MSC medium also enhancing lung repair after injury. Intratracheal MSC therapy enhanced recovery after ventilation-induced lung injury via a paracrine mechanism, and was as effective as intravenous MSC therapy.

Uncovering the neuroenteric–pulmonary axis: Vagal nerve stimulation prevents acute lung injury following hemorrhagic shock

Trauma/hemorrhagic shock (T/HS) induced gut injury is known to initiate a systemic inflammatory response which can lead to secondary lung injury. We have shown that vagal nerve stimulation (VNS) protects intestinal epithelial integrity after a severe burn insult. We hypothesize that VNS will protect the lung from injury following T/HS by preventing intestinal barrier failure. Male Balb/c mice were subjected to a T/HS model with and without cervical VNS. Intestinal injury was evaluated by measuring changes in gut barrier function and tight junction protein localization. Lung injury was evaluated using histology and markers of lung inflammation. Using NF-kB-luciferase (NF-kB-luc) transgenic mice, NF-kb-DNA binding was measured by photon emission analysis at 4 after injury. T/HS is associated gut injury characterized by histologic injury, increased epithelial permeability, and altered localization of gut tight junction proteins. Cervical VNS prevented the T/HS-induced changes in gut barrier integrity. Gut injury after T/HS was associated with acute lung injury at 24 h characterized by histologic injury, increased number of MPO positive stained cells and MPO enzymatic activity, and increased ICAM-1 expression in lung endothelium. VNS decreased T/HS-induced lung injury with a marked decrease in lung inflammation compared to T/HS alone. Lungs harvested from NF-kB-luc mice at 4h post VNS+T/HS demonstrated decreased DNA binding of NF-kB compared to T/HS alone as measured by changes in bioluminescence. VNS is effective in protecting against acute lung injury caused by hemorrhagic shock through its ability to prevent gut barrier dysfunction.

Anti‐IL‐5 attenuates activation and surface density of β2‐integrins on circulating eosinophils after segmental antigen challenge

IL-5 activates α(M) β(2) integrin on blood eosinophils in vitro. Eosinophils in bronchoalveolar lavage (BAL) following segmental antigen challenge have activated β(2) -integrins. To identify roles for IL-5 in regulating human eosinophil integrins in vivo. Blood and BAL eosinophils were analysed by flow cytometry in ten subjects with allergic asthma who underwent a segmental antigen challenge protocol before and after anti-IL-5 administration. Blood eosinophil reactivity with monoclonal antibody (mAb) KIM-127, which recognizes partially activated β(2) -integrins, was decreased after anti-IL-5. Before anti-IL-5, surface densities of blood eosinophil β(2) , α(M) and α(L) integrin subunits increased modestly post challenge. After anti-IL-5, such increases did not occur. Before or after anti-IL-5, surface densities of β(2) , α(M) , α(L) and α(D) and reactivity with KIM-127 and mAb CBRM1/5, which recognizes high-activity α(M) β(2) , were similarly high on BAL eosinophils 48 h post-challenge. Density and activation state of β(1) -integrins on blood and BAL eosinophils were not impacted by anti-IL-5, even though anti-IL-5 ablated a modest post-challenge increase on blood or BAL eosinophils of P-selectin glycoprotein ligand-1 (PSGL-1), a receptor for P-selectin that causes activation of β(1) -integrins. Forward scatter of blood eosinophils post-challenge was less heterogeneous and on the average decreased after anti-IL-5; however, anti-IL-5 had no effect on the decreased forward scatter of eosinophils in post-challenge BAL compared with eosinophils in blood. Blood eosinophil KIM-127 reactivity at the time of challenge correlated with the percentage of eosinophils in BAL post-challenge. IL-5 supports a heterogeneous population of circulating eosinophils with partially activated β(2) -integrins and is responsible for up-regulation of β(2) -integrins and PSGL-1 on circulating eosinophils following segmental antigen challenge but has minimal effects on properties of eosinophils in BAL. Dampening of β(2) -integrin function of eosinophils in transit to inflamed airway may contribute to the decrease in lung inflammation caused by anti-IL-5.

Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

Background/Aims: Bone marrow-derived cells (BMDCs) reduced mechanical and histologic changes in the lung in a murine model of silicosis, but these beneficial effects did not persist in the course of lung injury. We hypothesized that repeated administration of BMDCs may decrease lung inflammation and remodeling thus preventing disease progression. Methods: One hundred and two C57BL/6 mice were randomly divided into SIL (silica, 20 mg intratracheally [IT]) and control (C) groups (saline, IT). C and SIL groups were further randomized to receive BMDCs (2×10⁶ cells) or saline IT 15 and 30 days after the start of the protocol. Results: By day 60, BMDCs had decreased the fractional area of granuloma and the number of polymorphonuclear cells, macrophages (total and M1 phenotype), apoptotic cells, the level of transforming growth factor (TGF)-β‚ and types I and III collagen fiber content in the granuloma. In the alveolar septa, BMDCs reduced the amount of collagen and elastic fibers, TGF-β, and the number of M1 and apoptotic cells. Furthermore, interleukin (IL)-1β, IL-1R1, caspase-3 mRNA levels decreased and the level of IL-1RN mRNA increased. Lung mechanics improved after BMDC therapy. The presence of male donor cells in lung tissue was not observed using detection of Y chromosome DNA. Conclusion: repeated administration of BMDCs reduced inflammation, fibrogenesis, and elastogenesis, thus improving lung mechanics through the release of paracrine factors.

Impact of emerging pollutants on pulmonary inflammation in asthmatic rats: ethanol vapors and agglomerated TiO2 nanoparticles

Context: Titanium dioxide nanoparticles (nano-TiO2) and ethanol vapors are air contaminants with increasing importance. The presence of a pathological pulmonary condition, such as asthma, may increase lung susceptibility to such contaminants.Objective: This study aimed to investigate if exposure to inhaled ethanol vapors or nano-TiO2 can modulate the rat pulmonary inflammatory response resulting from an allergic asthmatic reaction.Materials and methods: Brown Norway rats were sensitized (sc) and challenged (15 min inhalation, 14 days later) with chicken egg ovalbumin (OVA). Leukocytes were counted in bronchoalveolar lavages (BAL) performed at 6, 24, 36, 48 and 72 h following the challenge and either after ethanol exposures (3000 ppm, 6 h/day, daily) or at 48 h (peak inflammation) for nano-TiO2 exposures (9.35 mg/m3 aerosol for 6 and 42 h after the OVA challenge). For the nano-TiO2 exposures, plasma and BAL cytokines were measured and lung histological analyzes were performed.Results: Exposure to ethanol did not significantly affect BAL leukocytes after OVA challenge. Exposure to nano-TiO2 significantly decreased BAL leukocytes compared to OVA-challenged controls. Plasma and BAL IL-4, IL-6, and INF-γ levels were also decreased in the nano-TiO2 group.Discussion: While ethanol vapors do not modify the pulmonary inflammation in rats during an asthmatic response, a surprising protective effect for agglomerated nano-TiO2 was observed. A putative mechanistic basis involving a decrease in the Th2 response caused by OVA is proposed.Conclusion: Allergic pulmonary inflammation is not up-regulated by inhalation of the pollutants ethanol and nano-TiO2. On the contrary, nano-TiO2 decreases lung inflammation in asthmatic rats.

3,4-Methylenedioxymethamphetamine (Ecstasy) Decreases Inflammation and Airway Reactivity in a Murine Model of Asthma

Objective: 3,4-Methylenedioxymethamphetamine (MDMA), or ecstasy, is a synthetic drug used recreationally, mainly by young people. It has been suggested that MDMA has a Th cell skewing effect, in which Th1 cell activity is suppressed and Th2 cell activity is increased. Experimental allergic airway inflammation in ovalbumin (OVA)-sensitized rodents is a useful model to study Th2 response; therefore, based on the Th2 skewing effect of MDMA, we studied MDMA in a model of allergic lung inflammation in OVA-sensitized mice. Methods: We evaluated cell trafficking in the bronchoalveolar lavage fluid, blood and bone marrow; cytokine production; L-selectin expression and lung histology. We also investigated the effects of MDMA on tracheal reactivity in vitro and mast cell degranulation. Results: We found that MDMA given prior to OVA challenge in OVA-sensitized mice decreased leukocyte migration into the lung, as revealed by a lower cell count in the bronchoalveolar lavage fluid and lung histologic analysis. We also showed that MDMA decreased expression of both Th2-like cytokines (IL-4, IL-5 and IL-10) and adhesion molecules (L-selectin). Moreover, we showed that the hypothalamus-pituitary-adrenal axis is partially involved in the MDMA-induced reduction in leukocyte migration into the lung. Finally, we showed that MDMA decreased tracheal reactivity to methacholine as well as mast cell degranulation in situ. Conclusions: Thus, we report here that MDMA given prior to OVA challenge in OVA-sensitized allergic mice is able to decrease lung inflammation and airway reactivity and that hypothalamus-pituitary-adrenal axis activation is partially involved. Together, the data strongly suggest an involvement of a neuroimmune mechanism in the effects of MDMA on lung inflammatory response and cell recruitment to the lungs of allergic animals.

Effects of Inhaled Nitric Oxide on Oxidative Stress and Histopathological and Inflammatory Lung Injury in a Saline-Lavaged Rabbit Model of Acute Lung Injury

Conventional mechanical ventilation (CMV) is fundamental in acute respiratory distress syndrome (ARDS) treatment. Inhaled nitric oxide (INO), an adjunctive therapy, has been used with ventilation in an attempt to improve oxygenation and reduce lung injury. To analyze the early effects of low INO dose on oxygenation, oxidative stress, inflammatory, and histopathological lung injury in a rabbit model of acute lung injury (ALI). This was a prospective, controlled, in vivo animal laboratory study. Forty rabbits were instrumented and ventilated at F(IO(2)) 1.0. ALI was induced by tracheal infusion of warm saline (30 mL/kg, 38°C) and lung oxidative stress was assessed by total antioxidant performance (TAP) assay. Animals were assigned to groups: control group (no. = 10, low tidal volume [V(T)] = 6 mL/kg, PEEP = 5 cm H(2)O), ALI without INO (no-INO group, no. = 10, low V(T) = 6 mL/kg, PEEP = 10 cm H(2)O), ALI plus INO (INO group, no. = 10, low V(T) = 6 mL/kg, PEEP = 10 cm H(2)O, INO = 5 ppm). Plateau pressure was limited to 30 cm H(2)O in all groups. Ten non-instrumented animals (healthy group) were studied for TAP assay. Ventilatory and hemodynamic parameters were recorded every 30 min for 4 hours. After lung injury, the instrumented groups were worse than the control group for P(aO(2)) (control group 438 ± 87 mm Hg, no-INO group 80 ± 13 mm Hg, INO group 81 ± 24 mm Hg, P < .001). The INO group showed decreased lung inflammation by leukocyte count in lung lavage fluid (no-INO group 4.8 ± 1.64, control group 0.16 ± 0.15, INO group 0.96 ± 0.35 polymorphonuclear cells × 10(6)/bronchoalveolar lavage fluid/lung, P < .001), decreased histopathological injury score (no-INO group 5 [range 1-16], INO group 2 [range 0-5], control group 0 [range 0-3], P < .001), and better lung protection against oxidative injury than the no-INO group (healthy group 68 ± 8.7, control group 66.4 ± 6.8, INO group 56.3 ± 5.1, no-INO group 45.9 ± 3.4 percent protection/g protein, P < .001). INO attenuates oxidative stress and histopathological and inflammatory lung injury in a saline-lavaged rabbit ALI model.

Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury

Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin–angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice—male (ACE2−/y) and female (ACE2−/−)—and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2−/y BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2−/y exposed to BLM, ACE2−/− exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

Resolvin D1 and Resolvin E1 Promote the Resolution of Allergic Airway Inflammation via Shared and Distinct Molecular Counter-Regulatory Pathways.

Resolvins are generated from omega-3 fatty acids during inflammatory responses in the lung. These natural mediators interact with specific receptors to decrease lung inflammation and promote its resolution in healthy tissues. There are several lung diseases of chronic inflammation that fail to resolve, most notable asthma. This common disorder has a lifetime prevalence of nearly 10% and is characterized, in part, by chronic, non-resolving inflammation of the airway. Pro-resolving mediators are generated during asthma; however, their biosynthesis is decreased in severe and uncontrolled asthma, suggesting that the chronic, adaptive inflammation in asthmatic airways may result from a resolution defect. This article focuses on recent insights into the cellular and molecular mechanisms for resolvins that limit adaptive immune responses in healthy airways.

Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat

BackgroundBone-marrow derived mesenchymal stem cells (MSCs) reduce the severity of evolving acute lung injury (ALI), but their ability to repair the injured lung is not clear. A study was undertaken...

Natural Surfactant Combined with Beclomethasone Decreases Lung Inflammation in the Preterm Lamb

Background: Natural surfactant combined with beclomethasone decreases pulmonary oxidative stress in preterm lambs with respiratory distress syndrome (RDS). Objectives: To test the hypothesis that this occurs through a decrease in pulmonary inflammation. Methods: Preterm lambs received 200 mg/kg of natural surfactant or 200 mg/kg of natural surfactant combined with 400 or 800 µg/kg of beclomethasone. Interleukin 8 (IL-8) and macrophage migration inhibitory factor (MIF) were assayed in bronchial aspirate samples and lung mechanics were evaluated. Results: IL-8 increased in all the groups, but the increase was lower in the groups treated with surfactant plus 400 and 800 µg/kg of beclomethasone. MIF decreased in the surfactant group, did not vary in the surfactant plus 400 µg/kg beclomethasone group, and decreased in the surfactant plus 800 µg/kg beclomethasone group. MIF concentration was higher in the surfactant plus 800 µg/kg beclomethasone group than in the other groups. Conclusions: Natural surfactant combined with beclomethasone at 800 µg/kg is effective in reducing lung inflammation in an animal model of RDS, thus explaining the associated decrease in lung oxidative stress. The increase in MIF in animals treated with surfactant plus 800 µg/kg of beclomethasone might be an important maturative and protective factor for neonatal lungs.

Local Tissue Expression of the Cell Death Ligand, Fas Ligand, Plays a Central Role in the Development of Extrapulmonary Acute Lung Injury

Indirect acute lung injury (ALI) is a common manifestation in critically ill patients. Using a model of indirect ALI in mice, our laboratory has shown that local/pulmonary inhibition of extrinsic death receptor protein (Fas) leads to a decrease in lung inflammation and improved survival. However, it is unknown if local, i.e., autocrine/paracrine, inhibition of Fas ligand (FasL) affects Fas-expressing target cells itself or blockade of the actions of a more distal/endocrine source of FasL that accounts for these findings. To examine this, we used a model of indirect ALI in mice (dual insult of hemorrhagic shock followed 24 h later by cecal ligation and puncture, in which animals received FasL small interfering RNA (siRNA) intratracheally (local silencing) or intravenously (systemic/distal delivery) after hemorrhage. After intratracheal delivery of FasL siRNA, there was a significant decrease in inflammatory cytokines, myeloperoxidase activity, and caspase 3 activity in lung tissue along with protein leak as compared with controls. There was no difference found in these various outcome markers between those treated with intravenously administered FasL siRNA versus controls. The observation that local silencing of FasL, as opposed to distal/systemic silencing, ameliorates the effects of indirect ALI suggests not only that FasL produced in an autocrine/paracrine fashion in local tissues has pathological consequences within the lungs, but also that FasL might be a valuable pulmonary therapeutic target.

Genetic ablation of phagocytic NADPH oxidase in mice limits TNFα-induced inflammation in the lungs but not other tissues

In vitro and limited in vivo evidence suggests that reactive oxygen species derived from NADPH oxidases (NOX-ROS) play an important role in inflammatory responses by enhancing the activity of redox-sensitive cell signaling pathways and transcription factors. Here, we investigated the role of NOX-ROS in TNFα-induced acute inflammatory responses in vivo, using mice deficient in the gp91(phox) (NOX2) or p47(phox) subunits of NADPH oxidase. Age- and body weight-matched C57BL/6J wild-type (WT) and gp91(phox) or p47(phox) knockout mice were injected intraperitoneally with 50 μg TNFα/kg bw or saline vehicle control and sacrificed at various time points up to 24 h. Compared to WT mice, gp91(phox -/-) mice exhibited significantly diminished (P<0.05) TNFα-induced acute inflammatory responses in the lungs but not other tissues, including heart, liver, and kidney, as evidenced by decreased activation of the redox-sensitive transcription factor NF-κB, and decreased gene expression of interleukin (IL)-1β, IL-6, TNFα, E-selectin, and other cellular adhesion molecules. Similar results were observed in p47(phox -/-) mice. Interestingly, decreased lung inflammation in knockout mice was accompanied by increased leukocyte infiltration into the lungs compared to other tissues. Our data suggest that phagocytic NOX-ROS signaling plays a critical role in promoting TNFα-induced, NF-κB-dependent acute inflammatory responses and tissue injury specifically in the lungs, which is effected by preferential leukocyte infiltration.

Estrogen Augments the Protection of Hypertonic Saline Treatment from Mesenteric Ischemia-Reperfusion Injury

Either estrogen or hypertonic saline (HTS) administration can decrease lung inflammation after ischemia-reperfusion. The present study investigated whether combined treatment with estrogen and HTS could provide further protection from mesenteric ischemia-reperfusion (MSIR) injury. Male C3H/HeOuJ mice were randomly segregated into the following groups: sham-operated (sham), vehicle treatment followed by MSIR (vehicle treated), estrogen treatment followed by MSIR (estrogen treated), HTS treatment and MSIR (HTS treated), and combined treatment of estrogen plus HTS and MSIR (combined treated). In MSIR, mice were subjected to mesenteric ischemia for 60 min followed by reperfusion for 30 min. The histology of the lung and the gut was obtained. Lung injury was evaluated by lung edema and myeloperoxidase (MPO) activity; lung protein expression of macrophage migration inhibitory factor (MIF), toll-like receptor-4 (TLR4), phosphorylated inhibitory κBα (p-IκBα), and inducible nitric oxide synthetase (iNOS) were assayed. Survival analysis was monitored after MSIR for 120 min. Compared with those in the sham-treated group, the lung water ratio, MPO activity, and expressions of MIF, TLR4, p-IκBα, and iNOS were significantly increased in the vehicle-treated group. Diminished MIF, TLR4, p-IκBα, and iNOS expressions were found in the estrogen-treated group, whereas suppression of p-IκBα and iNOS was found in the HTS-treated group. Treatment with estrogen or HTS decreased the lung water and MPO activity. The combined treatment of estrogen and HTS further significantly diminished p-IκBα and iNOS expression, lung edema, and MPO activity and improved the inflammation of the lung and the morphology of the gut in histology compared with the results of a single treatment of estrogen or HTS. Survival analysis showed significantly increased survival in the combination-treated group compared with survival in the HTS-treated group. In conclusion, compared with single-agent use, treatment combining estrogen and HTS further decreases lung p-IκBα and iNOS expressions, as well as the degree of lung injury. These effects may result in better rates of survival from MSIR injury.

Antioxidant and antiasthmatic effects of saucerneol D in a mouse model of airway inflammation

Chronic airway inflammation is a hallmark of asthma, which is an immune-based disease. We evaluated the ability of saucerneol D, a tetrahydrofuran-type sesquilignan isolated from Saururus chinensis, to regulate airway inflammation in an ovalbumin (OVA)-induced airway inflammation model. Furthermore, we determined whether heme oxygenase (HO)-1 was required for the protective activity of saucerneol D. The airways of OVA-sensitized mice exposed to an OVA challenge developed eosinophilia and mucus hypersecretion and exhibited increased cytokine levels. Mice were administered saucerneol D orally at doses of 20 and 40mg/kg once daily on days 26-30. Saucerneol D administered orally significantly inhibited the number of OVA-induced inflammatory cells and the production of immunoglobulin E as well as Th2-type cytokines. Histopathology studies revealed a marked decrease in lung inflammation and goblet cell hyperplasia after saucerneol D treatment. In addition, saucerneol D induced HO-1 and led to a marked decrease in OVA-induced reactive oxygen species and malondialdehyde and an increase in superoxide dismutase and glutathione in lung tissues. These antioxidant effects were correlated with HO-1 induction. In our experiments, saucerneol D treatment reduced airway inflammation and suppressed oxidative stress in an OVA-induced asthma model.

Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep

BackgroundIncreased pro-inflammatory cytokines in tracheal aspirates correlate with the development of BPD in preterm infants. Ventilation of preterm lambs increases pro-inflammatory cytokines and causes lung inflammation.ObjectiveWe tested the hypothesis that selective inhibitors of pro-inflammatory signaling would decrease lung inflammation induced by ventilation in preterm newborn lambs. We also examined if the variability in injury response was explained by variations in the endogenous surfactant pool size.MethodsDate-mated preterm lambs (n = 28) were operatively delivered and mechanically ventilated to cause lung injury (tidal volume escalation to 15 mL/kg by 15 min at age). The lambs then were ventilated with 8 mL/kg tidal volume for 1 h 45 min. Groups of animals randomly received specific inhibitors for IL-8, IL-1, or NF-κB. Unventilated lambs (n = 7) were the controls. Bronchoalveolar lavage fluid (BALF) and lung samples were used to quantify inflammation. Saturated phosphatidylcholine (Sat PC) was measured in BALF fluid and the data were stratified based on a level of 5 μmol/kg (~8 mg/kg surfactant).ResultsThe inhibitors did not decrease the cytokine levels or inflammatory response. The inflammation increased as Sat PC pool size in BALF decreased. Ventilated lambs with a Sat PC level > 5 μmol/kg had significantly decreased markers of injury and lung inflammation compared with those lambs with < 5 μmol/kg.ConclusionLung injury caused by high tidal volumes at birth were decreased when endogenous surfactant pool sizes were larger. Attempts to decrease inflammation by blocking IL-8, IL-1 or NF-κB were unsuccessful.

Particle-induced expression of SF20/IL25 is mediated by reactive oxygen species and NF-κB in alveolar macrophages

Bone marrow stroma-derived growth factor (SF20/IL25) regulates proliferation of lymphoid cells. We previously observed the upregulation of SF20/IL25 in alveolar macrophages treated with fine TiO2 particles and in a TiO2 particle-treated animal model. To identify the mechanism behind TiO2 particle-induced expression of SF20/IL25, we examined the dependence of the induction process on reactive oxygen species and on cytokine-mediated signaling transduction. For in vivo studies, TiO2 particles were intratracheally instilled in Sprague-Dawley rats. For in vitro studies, alveolar macrophages obtained from rat bronchoalveolar lavage cells were cultured in the presence of TiO2 particles. The antioxidant N-acetyl-L-cysteine (NAC) was used to block the formation of reactive oxygen species both in vivo and in vitro, and TPCK, SB203580, and GF10923X were used to inhibit signal transduction mediated by nuclear factor (NF)-κB, p38 MAP kinase, and protein kinase C, respectively, in vitro. In TiO2 particle-treated rats, intraperitoneal administration of NAC significantly decreased lung inflammation and attenuated the production of SF20/IL25 mRNA and protein. In TiO2 particle-stimulated alveolar macrophages, the upregulation of SF20/IL25 mRNA expression was abolished by NAC in a dose-dependent manner. The expression of SF20/IL25 mRNA in the stimulated macrophages was dose-dependently attenuated by TPCK, but not by SB203580 or GF10923X. Fine TiO2 particles stimulate alveolar macrophages to produce SF20/IL25 via the NF-κB-dependent generation of reactive oxygen species.

Molecular mechanisms of viral infection and propagation: An overview of the second Advanced Summer School in Africa

Molecular mechanisms of viral infection and propagation: An overview of the second Advanced Summer School in Africa