Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication - PubMed (original) (raw)

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Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication

Latoya N Johnson et al. Antioxid Redox Signal. 2009 Feb.

Abstract

Gap junction channels interconnect several different types of cells in the lung, ranging from the alveolar epithelium to the pulmonary vasculature, each of which expresses a unique subset of gap junction proteins (connexins). Major lung functions regulated by gap junctional communication include coordination of ciliary beat frequency and inflammation. Gap junctions help enable the alveolus to regulate surfactant secretion as an integrated system, in which type I cells act as mechanical sensors that transmit calcium transients to type II cells. Thus, disruption of epithelial gap junctional communication, particularly during acute lung injury, can interfere with these processes and increase the severity of injury. Consistent with this, connexin expression is altered during lung injury, and connexin-deficiency has a negative impact on the injury response and lung-growth control. It has recently been shown that alcohol abuse is a significant risk factor associated with acute respiratory distress syndrome. Oxidant stress and hormone-signaling cascades in the lung induced by prolonged alcohol ingestion are discussed, as well as the effects of these pathways on connexin expression and function.

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Figures

FIG. 1.

Intercellular communication in the lung. The lung consists of several distinct functional compartments. Shown in the inset are the terminal airspaces, alveoli, and bronchioles. (a) In the airways, including bronchioles, diffusion of IP3 through gap junctions enables the propagation of calcium waves, which help synchronize ciliary beating to allow directional transport of mucus. (b) The alveolar epithelium is a heterogeneous monolayer consisting of type II cells and type I cells. The alveolus acts as an integrated system in which type I cells respond to mechanical stimulation with an increase in intracellular calcium, which, in turn, is transmitted to type II cells via gap junctions to induce lamellar body fusion and secretion of pulmonary surfactant. Also shown is the alternative pathway, mediated by ATP secretion and paracrine stimulation via purinergic receptors. (c) In lung capillaries, transmission of calcium waves through pulmonary endothelial cell gap junctions upregulates the transport of P-selectin to the plasma membrane, thus transmitting a proinflammatory stimulus.

FIG. 2.

Oxidant and hormone stress responses in the alcoholic lung. Prolonged ethanol ingestion initiates and exacerbates oxidant stress via several pathways. Here is depicted a two-hit model for the role of alcoholic in ARDS. (1) Prolonged alcohol abuse causes direct oxidant stress because of the metabolism of ethanol to acetaldehyde. Ethanol also induces angiotensin II, which stimulates both the endothelium and epithelium to upregulate Nox activity. Oxidant stress depletes the alveolar epithelial glutathione pool, which induces cell damage and stimulates the cells to undergo an epithelial-to-mesenchyme transition (EMT) as a compensatory mechanism. Alveolar epithelial cells undergoing EMT increase production and secretion of TGF-β and have impaired alveolar barrier function, which adds further stress to the lung. (2) A second hit, such as direct trauma, infection, or sepsis, has an exaggerated effect on the alcoholic lung because of impaired alveolar epithelial function and the presence of a large pool of latent TGF-β, which is readily activated and exaggerates the normal injury response. Note the feedback loops in the diagram (dashed lines), indicating the potential for “runaway” activation of a deleterious injury response.

FIG. 3.

TGF-β1 inhibits gap junctional communication between alveolar epithelial cells. Primary rat type II cells were isolated and cultured for 6 days in minimal essential medium to produce a model type I cell monolayer. The cells were then treated with varying amounts of TGF-β1 for 16 h; then the extent of gap junctional communication was determined by visualizing the intercellular transfer of calcein microinjected into individual cells with fluorescence microscopy. Dye transfer was quantified by counting the number of calcein-labeled cells per microinjection. Data were combined from two independent experiments counting ≥20 microinjections/treatment. Increasing concentrations of TGF-β1 significantly decreased intercellular communication, as determined by t test (*p < 0.05).

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Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication - PubMed (original) (raw)