Prevented Lung Inflammation Research Articles

The prevention and treatment of DNA vaccination with encoding the cockroach allergen Bla g 1 on the allergic asthma

Cockroaches produce potent allergens that are an important cause of asthma. The hallmark feature of allergic asthma is abnormal expansionof Th2 cells in the lungs. We present a novel immunotherapeutic strategy using a Bla g 1 DNA vaccination that prevents lung inflammation, airwayobstruction, and hyperreactivity to allergen in a mouse modelof allergic disease, even afteranimals were presensitized and a Th2‐polarized immune responsewas established. Animals which received the DNA vaccine were protected against a following allergic sensitization with cockroach extract. The protective effect was characterized by suppression of cockroach allergen‐specific IgE production and enhanced IFN‐γ expression. In a therapeutic situation, treatment of sensitized animals with DNA vaccines decreased IgE production and drastically reduced anaphylactic activity as measured by enhanced IFN‐γ expression. Concerning the cellular immune response, DNA immunization induced a sustaining and dominant shift from a Th2 type response towards a balanced Th1/Th2 type response as indicated by increased IFN‐γ but decreased IL‐4 and IL‐5 levels in lymphoproliferation assays. Moreover, studies using bronchoalveolar lavage fluids of cockroach‐sensitized animals showed marked increase in imflammatory cells and eosinophils in contrast to BALF from Blag 1‐vaccinated animals. The histologic studies showed that the much reduced infiltration of inflammatory cells was observed in lung tissue of the gene vaccinated mice than that of the controls mice. The results demonstrate the allergen‐specific protective and therapeutic efficacy of a DNA vaccine encoding the cockroach allergen Bla g 1.

Formalin-Fixed Staphylococcus aureus Particles Prevent Allergic Sensitization in a Murine Model of Type I Allergy

Background: Bacterial infections are supposed to act counterregulatory to the development of allergen-specific Th2 immune responses. We analyzed whether administration of extracellular Staphylococcus aureus inhibited experimental sensitization against allergens. Methods: BALB/c mice were immunized with alum-adsorbed ovalbumin (OVA) together with formalin-fixed Staphylococcus particles. OVA-specific antibody production and cytokine synthesis by spleen cells was analyzed. Airway reactivity and cellular infiltration into the airways was assessed after intranasal challenge of mice with OVA. In addition, the capacity of Staphylococcus particles to modulate cytokine production by bone marrow-derived dendritic cells was analyzedin vitro. Results: Simultaneous application of OVA and Staphylococcus particles very efficiently inhibited production of specific IgE and IgG1 as well as secretion of IL-4 and IL-5 by splenocytes, while enhancing IgG2a formation and production of IFN-γ, indicating a shift from a Th2 response towards a Th1-biased response. This effect was not dependent on the expression of protein A by Staphylococcus. An enhanced frequency or activity of regulatory T cells after administration of Staphylococcus particles was not apparent. Treatment of mice with Staphylococcus particles during the sensitization phase prevented lung inflammation (airway hyperreactivity, eosinophilia) after local challenge with OVA. Culture of bone marrow-derived dendritic cells with Staphylococcus particles induced IL-12p35 and p40 mRNA expression as well as secretion of IL-12p70, and increased production of IL-10 mRNA and protein. Conclusions: Administration of formalin-fixed Staphylococcus particles induced Th1-biased immune responses and prevented allergic sensitization.

Airway Epithelium Controls Lung Inflammation and Injury through the NF-κB Pathway

Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.

Effects of Volatile Constituents of Rosemary Extract on Lung Inflammation Induced by Diesel Exhaust Particles

Epidemiological and experimental studies have implicated that diesel exhaust particles are involved in increases in morbidity and mortality from lung diseases. Recently, we have demonstrated that rosmarinic acid, a polyphenolic liquid component in perilla, inhibits lung inflammation induced by diesel exhaust particles in vivo, partly through its antioxidative property. We have also shown the antioxidative activities of volatile constituents of rosemary extract, the gaseous component in perilla, in vitro. The purpose of this study was to evaluate the effects of intratracheal administration of volatile rosemary extract on lung inflammation induced by diesel exhaust particles. ICR mice were treated with intratracheal administration of volatile rosemary extract before intratracheal exposure to diesel exhaust particles. Twenty-four hr later, diesel exhaust particles exposure elicited lung inflammation characterized by the infiltration of neutrophils and eosinophils, which was confirmed by cellular profile of bronchoalveolar lavage fluid and histological examination. Diesel exhaust particles enhanced the protein expressions of interleukin-1beta, macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractant in the lung. Pretreatment with rosemary extract significantly inhibited the diesel exhaust particles-induced lung inflammation. Rosemary extract treatment also suppressed the diesel exhaust particles-enhanced lung expression of macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractant. These results suggest that intratracheal administration of rosemary extract can prevent lung inflammation induced by diesel exhaust particles. The preventive effect is mediated, at least partly, through the inhibition of the enhanced lung expressions of macrophage inflammatory protein-1alpha, macrophage chemoattractant protein-1, and keratinocyte chemoattractants.

Modulation of airway inflammation and resistance in mice by a nicotinic receptor agonist

Nicotinic agonists, including 1,1-dimethyl-4-phenylpiperazinium (DMPP), have anti-inflammatory properties and in some instances smooth muscle relaxing effects. Since inflammation and airway smooth muscle contraction are two major components of asthma, the present authors investigated the effects of DMPP on airway inflammation and airway resistance in a mouse model of asthma. Mice were sensitised and challenged with ovalbumin (OVA) and treated either intraperitoneally or intranasally with DMPP. The effect of DMPP was tested on airway inflammation, airway resistance and on the increase of intracellular calcium in bronchial smooth muscle cells. DMPP given either during sensitisation, OVA challenges or throughout the protocol prevented lung inflammation and decreased the serum level of OVA specific immunoglobulin E. DMPP administration reduced the number of total cells, lymphocytes and eosinophils in the bronchoalveolar lavage (BAL) fluid. Intranasal DMPP administration was as effective as dexamethasone (DEXA) in reducing total cell count and eosinophil counts in BAL fluid. DMPP, but not DEXA, reduced tissue inflammation. Intranasal DMPP, given 10 min before the test, reduced airway responsiveness to metacholine. DMPP also reduced the increase in intracellular calcium in response to bradykinin. In conclusion, these results show that 1,1-dimethyl-4-phenylpiperazinium reduces lung inflammation and prevents airway hyperresponsiveness in the mouse model of asthma.

CC10 Administration to Premature Infants: In Search of the “Silver Bullet” to Prevent Lung Inflammation: Commentary on the article by Levine et al. on page 15

CC10 Administration to Premature Infants: In Search of the “Silver Bullet” to Prevent Lung Inflammation: Commentary on the article by Levine et al . on page 15

Blockade of Allergic Airway Inflammation Following Systemic Treatment with a B7-Dendritic Cell (PD-L2) Cross-Linking Human Antibody

We present a novel immunotherapeutic strategy using a human B7-DC cross-linking Ab that prevents lung inflammation, airway obstruction, and hyperreactivity to allergen in a mouse model of allergic inflammatory airway disease. Dendritic cells (DC) have the ability to skew the immune response toward a Th1 or Th2 polarity. The sHIgM12 Ab functions in vitro by cross-linking the costimulatory family molecule B7-DC (PD-L2) on DC up-regulating IL-12 production, homing to lymph nodes, and T cell-activating potential of these APCs. Using chicken OVA as a model Ag, the administration of sHIgM12 Ab to BALB/c mice blocked lung inflammation, airway pathology, and responsiveness to methacholine, even after animals were presensitized and a Th2-polarized immune response was established. This therapeutic strategy was ineffective in STAT4-deficient animals, indicating that IL-12 production is critical in this system. Moreover, the polarity of the immune response upon in vitro restimulation with Ag is changed in wild-type mice, with a resulting decrease in Th2 cytokines IL-4 and IL-5 and an increase in the immunoregulatory cytokine IL-10. These studies demonstrate that the immune response of hypersensitized responders can be modulated using B7-DC cross-linking Abs, preventing allergic airway disease upon re-exposure to allergen.

N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles.

Lung inflammation is a key response to increased levels of particulate air pollution (PM); however, the cellular mechanisms leading to this response are poorly understood. To determine whether oxidants are implicated in PM-dependent lung inflammation, we tested the ability of N-acetylcysteine (NAC) to prevent lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAPs). Adult Sprague-Dawley rats were exposed to either CAPs aerosols (CAPs mass concentration 1060 +/- 300 microg/m(3)) or filtered air (Sham controls) for 5 h. NAC-treated rats received 50 mg/kg (ip) NAC 1 h prior to exposure to CAPs. Oxidative stress and recruitment of inflammatory cells into bronchoalveolar lavage were evaluated 24 h after removal of the animals from the exposure chamber. Rats breathing CAPs aerosols showed significant oxidative stress, determined by the accumulation of thiobarbituric reactive substances (TBARS, 90 +/- 15 pmol/mg protein; sham control: 50 +/- 5 pmol/mg protein, p < 0.02) and oxidized proteins (1.6 +/- 0.4 nmol/mg protein, sham: 0.70 +/- 0.02 nmol/mg protein, p < 0.01) in their lungs. CAPs-induced oxidative stress was associated with increased numbers of polymorphonuclear leukocytes in bronchoalveolar lavage (BAL) (9 +/- 2%; sham: 1.6 +/- 0.5%, p < 0.001) and slight lung edema (wet/dry ratio: 4.77 +/- 0.03, sham: 4.69 +/- 0.02). No significant change was found in BAL protein concentration, total cell count, or lactate dehydrogenase (LDH) activity. NAC pretreatment effectively prevented CAPs-induced TBARS accumulation (30 +/- 10 pmol/mg protein, p < 0.006), lung edema (4.64 +/- 0.08, p < 0.05), and polymorphonuclear neutrophil (PMN) influx into the lungs (2.1 +/- 0.5%, p < 0.001), but did not alter the protein carbonyl content. Histological evaluation of tissue samples confirmed the BAL findings. CAPs-exposed animals showed slight bronchiolar inflammation and thickened vessels at the bronchiole, whereas NAC treated animals showed no histological alterations. Regression analyses showed strong associations between increased TBARS accumulation and the CAPs content of Al, Si, and Fe, and trends of association between carbonyl content and Cr and Na concentrations, and between BAL PMN count and Cr, Zn, and Na. These data demonstrate that oxidants are critical mediators of the inflammatory response elicited by PM inhalation.

Influence of Erythromycin Infusion on Establishment of Enteral Feeding in Preterm Infants &lt; 31 Weeks Gestation 65

Background/aims: Erythromycin is an analogue of the gastrointestinal hormone motilin. Preterm infants have demonstrated increased gastric motility after Erythromycin infusion but not increased duodenal motility1. We hypothesised that Erythromycin, when used as an antimicrobial agent in a randomised controlled trial to prevent lung inflammation attributable to Ureaplasma Urealyticum, would improve gastric emptying and decrease the time taken to establish full enteral feeding.

Immunization with Pseudomonas aeruginosa vaccines and adjuvant can modulate the type of inflammatory response subsequent to infection

Pseudomonas aeruginosa is the predominant pathogen in patients with cystic fibrosis (CF). To study the possibility of preventing lung inflammation and decreasing the progression of the infection by vaccination, we have developed a rat model of chronic P. aeruginosa lung infection. Rats were immunized with P. aeruginosa whole-cell sonicates, O-polysaccharide toxin A conjugate, an alginate-toxin A conjugate, or native alginate. Control animals received sterile saline or incomplete Freund's adjuvant (IFA). The macroscopic (mean score, 2.4 versus 2.7 to 3.2) (P < 0.05) and microscopic (mean score, 2.0 versus 2.1 to 2.8) pathologic abnormalities were less severe in the control rats injected with sterile saline than in the immunized rats and the IFA group. The more severe lung abnormalities observed in immunized rats could be due to the result of immune complex-mediated lung tissue damage. The histopathologic results in the saline control rats were characterized by acute inflammation dominated by numerous polymorphonuclear leukocytes surrounding the alginate beads (microcolonies), as in CF patients. In contrast, the inflammatory response in the IFA group and in the immunized rats had changed from an acute-type inflammation to a chronic-type inflammation dominated by mononuclear leukocytes and scattered granulomas. Cross-reacting antibodies were induced by the two alginate vaccines, and most immunized animals developed a significant (P < 0.001) antibody titer elevation (in enzyme-linked immunosorbent assay) of the immunoglobulin M (IgM), IgG, and IgA classes against the homologous antigens. The bacterial clearance was significantly (P < 0.05) more efficient in most immunized rats than in the control rats given sterile saline. The present study shows that none of the vaccines could completely prevent chronic lung inflammation 4 weeks after challenge. However, the changed pathologic condition in immunized rats to a chronic-type inflammation might be of great benefit in future management of CF patients since the developing lung tissue damage has been shown to be caused by polymorphonuclear leukocyte-released elastase.