Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation.

T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism.

Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma.

Excessive ROS promote allergic asthma, a condition characterized by airway inflammation, eosinophilic inflammation, and increased airway hyperreactivity (AHR). The mechanisms by which airway ROS are increased and the relationship between increased airway ROS and disease phenotypes are incompletely defined. Mitochondria are an important source of cellular ROS production, and our group discovered that Ca/calmodulin-dependent protein kinase II (CaMKII) is present in mitochondria and activated by oxidation.

Medication Desensitization: Characterization of Outcomes and Risk Factors for Reactions.

Background: Although its mechanisms are poorly understood, desensitization has been used to induce a temporary state of immune unresponsiveness in patients who have IgE-, non-IgE-, or pharmacologically mediated reactions when a drug has no alternatives.

Objectives: The purpose of this study was to characterize the outcomes and identify risk factors for reactions during drug desensitization.

Methods: A retrospective review of electronic medical records of adult patients undergoing drug desensitization from January 1, 2011, to December 31, 2013, was conducted in 2 intensive care units at a tertiary medical center.

Hyaluronan and Its Heavy Chain Modification in Asthma Severity and Experimental Asthma Exacerbation.

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI), which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity.

Glutathione S-transferase M1 modulates allergen-induced NF-κB activation in asthmatic airway epithelium.

Background: Glutathione S-transferase M1 (GSTM1) is a phase II enzyme and regulator of inflammatory signaling in airway epithelial cells. We have found upregulation of neutrophilic airway inflammation in atopic asthmatics expressing GSTM1 gene (GSTM1+) compared to GSTM1null asthmatics. We hypothesized that GSTM1 modulates NF-κB activation in bronchial epithelium in atopic asthmatics.

Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.

Rationale: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function.

CaMKII is essential for the proasthmatic effects of oxidation.

Increased reactive oxygen species (ROS) contribute to asthma, but little is known about the molecular mechanisms connecting increased ROS with characteristic features of asthma. We show that enhanced oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase (ox-CaMKII) in bronchial epithelium positively correlates with asthma severity and that epithelial ox-CaMKII increases in response to inhaled allergens in patients. We used mouse models of allergic airway disease induced by ovalbumin (OVA) or Aspergillus fumigatus (Asp) and found that bronchial epithelial ox-CaMKII was required to increase a ROS- and picrotoxin-sensitive Cl(-) current (ICl) and MUC5AC expression, upstream events in asthma progression.

Glutathione S-transferase P1 Ile105Val polymorphism modulates allergen-induced airway inflammation in human atopic asthmatics in vivo.

Background: Glutathione S-transferase P1 is a Phase II cytoprotective and detoxifying enzyme that is widely expressed in human airways. The glutathione S-transferase P1 Ile105Val polymorphism has been linked with atopic disorders and asthma. Yet, little remains known about the regulation of allergic inflammation by glutathione S-transferase P1 in human asthmatics.

Exhaled breath condensate formate after inhaled allergen provocation in atopic asthmatics in vivo.

Objective: The dual actions of S-nitrosoglutathione reductase comprise reduction of S-nitrosoglutathione, a potent endogenous airway smooth muscle relaxant that is depleted in asthmatics, and detoxification of formaldehyde to formate. Airway formate production is increased in children with asthma, suggesting increased activity of S-nitrosoglutathione reductase. We determined formate in exhaled breath condensate from adult atopic asthmatics with asthma exacerbation produced by inhaled allergen in vivo,

Methods: Twenty-two adult atopic asthmatics underwent inhaled allergen challenge using specific allergen.

Asthmatic airway neutrophilia after allergen challenge is associated with the glutathione S-transferase M1 genotype.

Rationale: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity.

Iloprost inhalation in mild asthma.

Objective: To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma.

Methods: Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.

Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress.

Background: Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury.

Methods: LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h.

Natural-source d-α-tocopheryl acetate inhibits oxidant stress and modulates atopic asthma in humans in vivo.

Background: Asthma is associated with oxidant stress and diminished antioxidant defenses. Yet, the mechanistic role of oxidant stress and antioxidant supplementation in human asthmatics remains uncertain. We determined the effect of high doses of the antioxidant natural-source d-α-tocopheryl acetate for 16 weeks on allergen-induced airway oxidant stress, inflammation, and bronchial responsiveness to methacholine and allergen in atopic asthmatics in vivo.

Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo.

Asthma is a chronic inflammatory airway disease associated with increased generation of reactive oxidant species and disturbed antioxidant defenses. NRF2 is the master transcription factor that regulates the expression of Phase II antioxidant and detoxifying enzymes. Disruption of NRF2 augments oxidative stress and inflammation in a mouse model of asthma, suggesting a protective role for NRF2 in the lungs in vivo.

Eosinophil and neutrophil extracellular DNA traps in human allergic asthmatic airways.

Background: Asthma is a heterogeneous inflammatory airway disorder that involves eosinophilic and noneosinophilic phenotypes. Unlike in healthy lungs, eosinophils are often present in atopic asthmatic airways, although a subpopulation of asthmatic subjects predominantly experience neutrophilic inflammation. Recently, it has been demonstrated that eosinophils and neutrophils generate bactericidal extracellular traps consisting of DNA and cytotoxic granule proteins.

Effect of allergen challenge on the percentage of natural killer T cells in patients with atopic asthma.

Background: Invariant natural killer T (iNKT) cells produce cytokines that can influence the immune response to infection or allergen. Controversy surrounds their role in exacerbations of human atopic asthma.

Objectives: To determine the effect of allergen challenge on iNKT cells' mobilization to the airways and blood and to establish the relationship between airway iNKT cells and bronchial sensitivity to methacholine and allergen in patients with atopic asthma.

Use of olopatadine ophthalmic solution and reactivity of histamine skin testing.

The significant morbidity of allergic rhinitis and allergic conjunctivitis necessitates that diagnosis must be as accurate as possible. However, the very drugs used to treat allergic symptoms have been found to suppress histamine-induced skin testing, making the diagnosis very challenging. Oral formulations of antihistamines are well known to diminish skin test reactivity, but ocular application has never been studied to our knowledge.

Oxidant stress modulates murine allergic airway responses.

The allergic inflammation occurring in asthma is believed to be accompanied by the production of free radicals. To investigate the role of free radicals and the cells affected we turned to a murine model of allergic inflammation produced by sensitization to ovalbumin with subsequent aerosol challenge. We examined oxidant stress by measuring and localizing the sensitive and specific marker of lipid peroxidation, the F2-isoprostanes.

The prostaglandin E agonist, misoprostol, inhibits airway IL-5 production in atopic asthmatics.

Background: Prostaglandin E2 is a potent immunomodulator that inhibits the early and late bronchoconstriction to inhaled allergen, as well as inhibiting the acute allergen-induced release of mediators into the human airway. To determine if the stable prostaglandin E agonist misoprostol could alter the late allergic formation of mediators we measured the appearance of eosinophils and key cytokines in the bronchoalveolar lavage fluid 24 h after allergen instillation.

Methods: Six atopic asthmatics underwent bronchoscopy, alveolar lavage and antigen instillation followed 24 h later by bronchoalveolar lavage.

Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis.

Background: Prostanoids are known to participate in the process of fibrogenesis. Because lung fibroblasts produce prostanoids and are believed to play a central role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), we hypothesized that fibroblasts (HF) cultured from the lungs of patients with IPF (HF-IPF) have an altered balance between profibrotic (thromboxane [TX]A2) and antifibrotic (prostacyclin [PGI2]) prostaglandins (PGs) when compared with normal human lung fibroblasts (HF-NL).

Methods: We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1beta stimulation.

Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice.

Nonselective cyclooxygenase (COX) inhibition during allergic sensitization with ovalbumin in a murine model leads to an increase in the Type 2 cytokines interleukin-5 (IL-5) and IL-13; however, the effect of selective COX-1 and COX-2 inhibitors on these cytokines is unknown. We found that COX-1 protein was constitutively expressed in lung tissue. Expression of COX-1 protein did not increase with ovalbumin sensitization, but expression of COX-2 protein did.

Late asthmatic reactions provoked by intradermal injection of T-cell peptide epitopes are not associated with bronchial mucosal infiltration of eosinophils or T(H)2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid.

Background: Isolated late asthmatic reactions can be provoked by intradermal challenge of allergen-derived T-cell peptide epitopes.

Objective: The purpose of this study was to determine whether the isolated LAR is associated with the local accumulation of inflammatory cells, the expression of T(H)2 cytokines, and the production of pharmacologic mediators.

Methods: A randomized, placebo-controlled, crossover study design was used.

Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells.

Although pulmonary inflammation is an important pathologic event in cystic fibrosis (CF), the relationship between expression of the CF gene and the inflammatory response is unclear. We studied tumor necrosis factor (TNF) alpha and IL-1beta stimulated production of IL-6 and IL-8 by CF, corrected CF, and normal human bronchial epithelial cells in culture. During the first 24 hours of TNFalpha stimulation, CF cells produced significantly more IL-8 than normal or corrected CF cells.