Inflammatory mediators of asthma: an update.

Cytokines are usually extracellular signalling proteins, usually less than 80 kD in size, and many are glycosylated. They are produced by many different cell types that are involved in cell-to-cell interactions acting through specific receptors on the surface of target cells. Cytokines usually have an effect on closely adjacent cells and therefore function in a predominantly paracrine fashion, although they may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). Cytokines may be regarded as a mechanism for cell-cell communication, and within this group may be included growth factors and cytokines with primarily chemoattractant properties (chemokines). They act on target cells to cause a wide array of cellular functions including activation, proliferation, chemotaxis, immunomodulation, release of other cytokines or mediators, growth and cell differentiation, and apoptosis. Cytokines were originally characterised (and named) according to some aspect of their functional activity that was initially discovered, but the cloning of the genes for these cytokines has now provided a better insight into their classification and grouping. It is apparent that there is a wide pleiotropy and element of redundancy in the cytokine family in that each cytokine has many overlapping functions, with each function potentially mediated by more than one cytokine.

The effect of an individual cytokine in the context of disease may not be easy to predict because it may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine. The effects of cytokines are mediated by binding to cell surface high affinity receptors usually present in low numbers. The number of these receptors can be upregulated with cell activation, and there the effect of a cytokine may depend on the modulation of its receptors. Cytokines themselves may induce the expression of receptors which may …

https://thorax.bmj.com/content/thoraxjnl/54/9/825.full.pdf

Cytokines in asthma

The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.

Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury.

The culture of human airway epithelial cells has played an important role in advancing our understanding of the metabolic and molecular mechanisms underlying normal function and disease pathology of airway epithelial cells. Recent advances in culturing primary epithelial cells and the development of transformed airway epithelial cell lines have been particularly important in enhancing our understanding of the pathology associated with cystic fibrosis and lung cancer. The establishment of conditions that enhance the proliferative capacity of airway epithelial cells in primary culture was the first technical hurdle overcome in the development of in vitro culture systems. Research is now being geared toward the development of cell culture conditions that facilitate the expression in culture of the differentiated characteristics found in the native epithelium. Aside from the advances that have been made in defining the growth media and extracellular matrixes that enhance the expression of differentiated features, the use of an air-liquid interface has been a significant advance in the culture of airway epithelial cells. The implementation of the in vitro cell culture systems that have now been established and the research into optimizing the conditions for the growth of airway epithelial cells have been and will continue to be essential in the development of therapies for airway disease.

Culture and transformation of human airway epithelial cells

Increased Th2 cytokine production in asthma is widely accepted, but excess production by asthmatic human airway CD4+ T cells has not been demonstrated, nor has a relationship with disease severity. The importance of airway CD8+ T cell type 1 and type 2 cytokine production in asthma is unknown. We investigated frequencies of IFN-γ, interleukin (IL)-4 and IL-5 producing CD4+ and CD8+ blood and sputum T cells from normal subjects and subjects with asthma and compared between cell subsets, subject groups, and body compartments with and without in vitro stimulation and investigated relationships between cytokine production and asthma severity. Production of IL-4, IL-5, and IFN-γ by unstimulated sputum CD4+ and CD8+ T cells was increased in subjects with asthma and related to disease severity, more for CD8+ than for CD4+ T cells. Frequencies of sputum CD8+ T cells producing type 1 and type 2 cytokines were similar to those of CD4+ T cells. In vitro stimulation polarized peripheral blood cytokine production towa...

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Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+ and CD8+ T cells in atopic asthma

To evaluate the factors controlling migration of leukocytes into pulmonary airway epithelium, we determined the biochemical mechanisms responsible for the regulation of intercellular adhesion molecule-1 (ICAM-1) expression on cultured monolayers of human tracheal epithelial cells (HTECs) or SV40 virus-transformed human bronchial epithelial cells (BEAS-2B). Validation experiments with human umbilical vein endothelial cells (HUVECs) demonstrated little detectable ICAM-1 expression on unstimulated cells or on cells incubated with interferon-gamma (IFN-gamma), but HUVEC monolayers responded to interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) with significant increases in ICAM-1 and ICAM-1-dependent adherence of polymorphonuclear leukocytes (PMNs). HTEC monolayers also exhibited no significant basal ICAM-1 expression but, in contrast to HUVEC monolayers, had marked increases in ICAM-1 expression and ICAM-1-dependent PMN adherence only after incubation with IFN-gamma (and not after IL-1 beta or TNF-alpha) treatment. BEAS-2B cells also exhibited relatively selective IFN-gamma stimulation of ICAM-1 expression and ICAM-1-dependent PMN adherence but (like late passage HTEC) showed significant basal ICAM-1 expression. Differences in IFN-gamma effect on ICAM-1 levels between HUVEC and HTEC monolayers were not due to differences in number or responsiveness of IFN-gamma receptors, because both cell types exhibited a similar number of receptors and other IFN-gamma-dependent responses of HUVECs remained active. In all analyses, ICAM-1 mRNA levels correlated closely with detection of ICAM-1 on the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)

B. T. Keller

Papers

Selective induction of intercellular adhesion molecule-1 by interferon-gamma in human airway epithelial cells