Comments for:
Abstract
Propagation of inflammatory signals from the airspace to the vascular space is pivotal in lung inflammation, but mechanisms of intercompartmental signaling are not understood. To define signaling mechanisms, we microinfused single alveoli of blood-perfused rat lung with TNF-α, and determined in situ cytosolic Ca2+ concentration ([Ca2+]i) by the fura-2 ratio method, cytosolic phospholipase A2 (cPLA2) activation and P-selectin expression by indirect immunofluorescence. Alveolar TNF-α increased [Ca2+]i and activated cPLA2 in alveolar epithelial cells, and increased both endothelial [Ca2+]i and P-selectin expression in adjoining perialveolar capillaries. All responses were blocked by pretreating alveoli with a mAb against TNF receptor 1 (TNFR1). Crosslinking alveolar TNFR1 also increased endothelial [Ca2+]i. However, the endothelial responses to alveolar TNF-α were blocked by alveolar preinjection of the intracellular Ca2+ chelator BAPTA-AM, or the cPLA2 blockers AACOCF3 and MAFP. The gap-junction uncoupler heptanol had no effect. We conclude that TNF-α induces signaling between the alveolar and vascular compartments of the lung. The signaling is attributable to ligation of alveolar TNFR1 followed by receptor-mediated [Ca2+]i increases and cPLA2 activation in alveolar epithelium. These novel mechanisms may be relevant in the alveolar recruitment of leukocytes.
Authors
Wolfgang M. Kuebler, Kaushik Parthasarathi, Ping M. Wang, Jahar Bhattacharya
Arachidonic acid in intercompartmental communication: extending the model
Submitter: Mariano Sánchez Crespo | mscres@ibgm.uva.es
IBGM, 47005-Valladolid, Spain
Published April 24, 2000
The paper by Kuebler et al., (J. Clin. Invest. 105:905-913, 2000), addressing the central role of arachidonic acid in the biochemical signaling between gas and blood compartments of the lung raises important issues regarding the interactions between lipid (eicosanoids, lysophosphatidic acid, platelet-activating factor) and polypeptide mediators of inflammation (e.g., the cytokine network). As pointed out by M. Peters- Golden in the Commentary enclosed in the same issue of the Journal, these classes of factors have traditionally been regarded as activating distinct inflammatory pathways. In this regard, I want to extend the paradigm to both agonists and xenobiotics in the lung, and also, to propose another system in which arachidonic acid could exert a similar justacrine/paracrine signaling effect involving different cell types. First, I wonder if in the model of Kuebler et al., agonists acting on G-protein coupled receptors, e.g., the chemoattracts, might initiate a similar signaling pathway. In fact, phosphoinositide-dependent Ca2+ mobilization by these agonists is a more prominent event than it is in response to engagement of TNFR1. This ability is enhanced in the presence of compounds such as cytochalasin B and low concentrations of thapsigargin, since both compounds extend the duration of Ca2+-transients and enhance the production of both arachidonic acid and platelet- activating factor by leukocytes (1). A similar role for arachidonic acid in intercompartmental communication could be envisaged in the nervous system, since astrocytes display a connecting role between vessels and neurones, control the chemical environment of neurons and its ability to transduce specific signals, and facilitate the migration of leukocytes by expressing adhesion molecules. Interestingly, astrocytes of the gray matter have an active metabolism of arachidonic acid and are endowed with high amounts of cytosolic phospholipase A2 functionally coupled to receptors for neurotransmitters, thrombin, secretory phospholipase A2, and TNF-a (2). All of these agonists activate cytosolic phospholipase A2, as judged from the band-shift characteristic of the phosphorylation of its Ser-505 by MAP -kinase and the release of arachidonic acid. However, depending on the agonists, this effect may be associated with a different pattern of activation of the elements of the MAP kinase family. In the case of TNF, the activation of cystosolic phospholipase A2 is associated with an early the activation of c-Jun N-terminal kinase and is followed by a delayed conversion of arachidonic acid into cyclooxygenase products associated to cycloogygenase -2 induction (3
Mariano Sánchez Crespo, Marita Hernández and María Luisa Nieto
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)