Luis M. Teran

Rhinovirus Infection Induces Major Histocompatibility Complex Class I and Costimulatory Molecule Upregulation on Respiratory Epithelial Cells

Human respiratory epithelial cells may act as antigen-presenting cells during respiratory viral infections. In addition to major histocompatibility complex (MHC) molecules, antigen presentation requires participation of costimulatory molecules. Here the authors investigated class I and class II antigens and B7-1 and B7-2 costimulatory molecule expression in human A549 pulmonary epithelial cells and primary bronchial epithelial cells (HBECs) at baseline and after rhinovirus infection. Constitutive expression of MHC class I and B7-1 molecules was observed on both cell types. MHC class I molecules were up-regulated by rhinovirus infection, while B7-1 was up-regulated only on A549 cells. B7-2 molecules were constitutively expressed at a low level and were up-regulated by rhinovirus only on HBECs. Rhinovirus induction of antigen-presenting molecule expression on A549 cells was accompanied by cellular activation in terms of induction of release of the chemokines RANTES and Groalpha. These data show that respiratory epithelium expresses full antigen-presentation machinery and that rhinovirus infection up-regulates this expression.

Identification of neutrophil chemotactie factors in bronchoalveolar lavage fluid of asthmatic patients

Background Although neutrophils have been implicated in bronchial asthma, the mechanism(s) which bring these cells into the airways is poorly understood.

Th2- and to a Lesser Extent Th1-Type Cytokines Upregulate the Production of both CXC (IL-8 and Gro-Alpha) and CC (RANTES, Eotaxin, Eotaxin-2, MCP-3 and MCP-4) Chemokines in Human Airway Epithelial Cells

Background: Both CXC and CC chemokines play an important role in leukocyte recruitment. However, a systematic examination of their production by human airway epithelial cells (HAECs) has not been carried out. The objective of this study was to investigate whether Th1- and Th2-type cytokines regulate chemokine production in HAECs. Methods: HAECs were grown from both nasal and bronchial tissue and subsequently stimulated with either Th1- or Th2-type cytokines. Results: Constitutive mRNA expression for gro-alpha, IL-8 and RANTES was seen in both human nasal and human bronchial epithelial cells. IL-4 was the strongest stimulus for both gene expression and protein production of the chemokines RANTES, IL-8 and gro-alpha, while both IL-13 and IFN-gamma were weaker inducers of these chemokines, with the exception of gro-alpha (IL-13 was a strong stimulus for gro-alpha production). TNF-alpha synergized with IL-4, and to a lesser extent with IFN-gamma and IL-13, to release RANTES, IL-8 and gro-alpha. IL-4 and to a lesser extent IL-13 and IFN-gamma stimulated the production of MCP-3 and -4, eotaxin and eotaxin-2 immunoreactivities. However, no induction of the mRNAs encoding these chemokines was observed, suggesting that they may be released from a preformed pool within the HAECs. Conclusion: These findings suggest that when released into the airways, Th2- and to a lesser extent Th1-type cytokines may stimulate recruitment of eosinophils and neutrophils through the release of CC (RANTES, MCP-3 and -4, eotaxin and eotaxin-2) and CXC chemokines (gro-alpha and IL-8).

Cellular and mediator responses twenty-four hours after local endobronchial allergen challenge of asthmatic airways☆☆☆★★★

The effects of acute allergen exposure on bronchoalveolar lavage cells and mediators and mucosal inflammatory cells were evaluated in 10 subjects with atopic asthma who underwent lavage and biopsy 24 hours after segmental endobronchial allergen challenge. Increased numbers of bronchoalveolar lavage eosinophils were retrieved from the allergen-challenged sites compared with the saline-challenged sites (mean 21.4 vs 1.5 x 10(3) cells/ml; p < 0.02). Numbers of neutrophils and proportions of CD4+, CD8+, CD25+, and HLA-DR+ T cells were similar at the saline- and allergen-challenged sites. In contrast to the bronchoalveolar lavage findings, eosinophil numbers were not increased in the bronchial submucosa or epithelium. There was also no significant difference in neutrophils, mast cells, CD3+, CD4+, or CD8+ T cells in the submucosa after allergen challenge, but the number of activated (CD25+) T lymphocytes in the mucosa did increase after allergen challenge. Allergen challenge did not induce any significant change in endothelial expression of P-selectin, E-selectin, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1. CD11a+ and very late antigen-4+ cell numbers were similar in the saline- and allergen-challenged sites. This study suggests that in patients with very mild asthma, local allergen challenge induces persistent bronchoalveolar lavage eosinophilia, but the recruitment process seems to have diminished or ceased by 24 hours.

Cultured nasal polyps from nonatopic and atopic patients release RANTES spontaneously and after stimulation with phytohemagglutinin

BACKGROUND Eosinophil infiltration of tissue is a hallmark of nasal polyposis in both nonatopic and atopic patients. These cells are thought to play a key role in the nasal polyp inflammatory process. OBJECTIVE The objective of this study was to investigate whether cultured nasal polyps derived from nonatopic and atopic patients release RANTES both spontaneously and after phytohemagglutinin (PHA) stimulation. METHODS Nasal polyps were obtained from 12 subjects (6 nonatopic and 6 atopic), cut into 2 to 3 mm large specimens, and cultured for 48 hours with or without PHA. RANTES was measured in the culture supernatant by ELISA (R&D Systems, U.K.). RESULTS Immunoreactive RANTES was found to be present in the culture supernatant of nasal polyps derived from both nonatopic and atopic patients with no difference between the two groups (median: 3.8 vs 2.9 pg/mg/ml). On incubation with PHA, nasal polyps from both nonatopic and atopic patients released sevenfold and 11-fold greater amounts of RANTES than unstimulated samples. As determined by immunohistochemistry, RANTES was localized to the vascular endothelium in nasal polyps from both groups of patients. CONCLUSIONS This study demonstrates that cultured nasal polyps derived from both nonatopic and atopic patients release RANTES spontaneously and after PHA stimulation. This observation and the finding that RANTES is present in nasal polyp endothelial cells suggest that this chemokine may be an important mediator of eosinophil and lymphocyte recruitment in both nonatopic and atopic nasal polyposis.

Chemokine (C-X-C Motif) Ligand 12/Stromal Cell-Derived Factor-1 Is Associated With Leukocyte Recruitment in Asthma

BACKGROUND Asthma is characterized by allergic airway inflammatory response involving extensive leukocyte infiltration. The stromal cell-derived factor (SDF)-1 or chemokine (C-X-C motif) ligand 12 (CXCL12) attracts a number of cells, including resting T lymphocytes, monocytes, CD34(+) stem cells, basophils, and mature eosinophils. To date, however, the potential role of CXCL12/SDF-1 in relation to leukocyte recruitment in asthma has not been previously examined, to our knowledge. METHODS Levels of CXCL12/SDF-1 in the BAL fluid (BALF) of 15 subjects with asthma and 13 healthy subjects were measured by enzyme-linked immunosorbent assay. Immunohistochemistry was performed to identify the cellular source of this chemokine. RESULTS CXCL12/SDF-1 concentrations were significantly elevated in BALF from subjects with asthma compared with normal subjects (median 845 pg/mL, range, 296-1,700 pg/mL vs median 55 pg/mL, range 25-97 pg/mL; P < .001). Concentrations of CXCL12/SDF-1 correlated with macrophages (r = 0.728, P < .01), lymphocytes (r = 0.651, P < .01), and eosinophils (r = 0.765, P < .01). By immunohistochemistry, CXCL12/SDF-1 was localized to the airway epithelium and to a lesser extent to mononuclear cells. CONCLUSION CXCL12/SDF-1 is released in high concentration in BALF of patients with asthma. The finding that concentrations of this chemokine correlated with leukocyte numbers in BALF suggests that this chemokine may contribute to the cell recruitment in asthma.

Neutrophil influx and interleukin-8 release after segmental allergen or saline challenge in asthmatics

Neutrophils have been associated with the late asthmatic reaction. However, their role in this disease is not well understood. In this study, we have measured neutrophil influx and release of interleukin-8 into asthmatic airways after endobronchial challenge with either allergen or saline solution.

Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD)

Aspirin exacerbated respiratory disease (AERD) is a distinct clinical entity characterized by eosinophilic rhinosinusitis, asthma and often nasal polyposis. Exposure to aspirin or other nonsteroid anti-inflammatory drugs (NSAIDs) exacerbates bronchospasms with asthma and rhinitis. Disease progression suggests a skewing towards TH2 type cellular response along with moderate to severe eosinophil and mast cell infiltration. Alterations in upper and lower airway cellular milieu with abnormalities in eicosanoid metabolism and altered eicosanoid receptor expression are the key features underlying AERD pathogenesis. Dysregulation of arachidonic acid (AA) metabolism, notably reduced prostaglandin E2 (PGE2) synthesis compared to their aspirin tolerant counterpart and relatively increased PGD2 production, a TH2/eosinophil chemoattractant are reported in AERD. Underproduced PGE2 is metabolized by overexpression of 15 prostaglandin dehydrogenase (15-PGDH) to inactive products further reducing PGE2 at real time. This relives the inhibitory effect of PGE2 on 5-lipoxygenase (5-LOX) resulting in overproduction of cysteinyl leukotrienes (CysLTs). Diminished formation of CysLT antagonists called lipoxins (LXs) also augments CysLTs responsiveness. Occasional intake of NSAIDs favors even more 5-LOX product formation, further narrowing the bronchoconstrictive bottle neck, resulting in acute asthmatic exacerbations along with increased mucus production. This review focuses on abnormalities in biochemical and molecular mechanisms in eicosanoid biosynthesis, eicosanoid receptor dysregulation and associated polymorphisms with special reference to arachidonic acid metabolism in AERD.

Chemokines and Their Receptors in the Allergic Airway Inflammatory Process

The development of the allergic airway disease conveys several cell types, such as T-cells, eosinophils, mast cells, and dendritic cells, which act in a special and temporal synchronization. Cellular mobilization and its complex interactions are coordinated by a broad range of bioactive mediators known as chemokines. These molecules are an increasing family of small proteins with common structural motifs and play an important role in the recruitment and cell activation of both leukocytes and resident cells at the allergic inflammatory site via their receptors. Trafficking and recruitment of cell populations with specific chemokines receptors assure the presence of reactive allergen-specific T-cells in the lung, and therefore the establishment of an allergic inflammatory process. Different approaches directed against chemokines receptors have been developed during the last decades with promising therapeutic results in the treatment of asthma. In this review we explore the role of the chemokines and chemokine receptors in allergy and asthma and discuss their potential as targets for therapy.

Respiratory proteomics: from descriptive studies to personalized medicine.

Respiratory diseases are highly prevalent and affect humankind worldwide, causing extensive morbidity and mortality with the environment playing an important role. Given the complex structure of the airways, sophisticated tools are required for early diagnosis; initial symptoms are nonspecific, and the clinical diagnosis is made frequently late. Over the past few years, proteomics has made high technological progress in mass-spectrometry-based protein identification and has allowed us to gain new insights into disease mechanisms and identify potential novel therapeutic targets. This review will highlight the contributions of proteomics toward the understanding of the respiratory proteome listing potential biomarkers and its potential application to the clinic. We also outline the contributions of proteomics to creating a personalized approach in respiratory medicine.