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Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Kaushik Parthasarathi, … , Andrew Issekutz, Jahar Bhattacharya
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2193-2200. https://doi.org/10.1172/JCI26605.
View: Text | PDF | Corrigendum
Research Article Pulmonology

Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries

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Abstract

Acute lung injury (ALI), which is associated with a mortality of 30–40%, is attributable to inflammation that develops rapidly across the lung’s vast vascular surface, involving an entire lung or even both lungs. No specific mechanism explains this extensive inflammatory spread, probably because of the lack of approaches for detecting signal conduction in lung capillaries. Here, we addressed this question by applying the photolytic uncaging approach to induce focal increases in Ca2+ levels in targeted endothelial cells of alveolar capillaries. Uncaging caused Ca2+ levels to increase not only in the targeted cell, but also in vascular locations up to 150 μm from the target site, indicating that Ca2+ was conducted from the capillary to adjacent vessels. No such conduction was evident in mouse lungs lacking endothelial connexin 43 (Cx43), or in rat lungs in which we pretreated vessels with peptide inhibitors of Cx43. These findings provide the first direct evidence to our knowledge that interendothelial Ca2+ conduction occurs in the lung capillary bed and that Cx43-containing gap junctions mediate the conduction. A proinflammatory effect was evident in that induction of increases in Ca2+ levels in the capillary activated expression of the leukocyte adherence receptor P-selectin in venules. Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed. Gap junctional mechanisms require further consideration in the understanding of ALI.

Authors

Kaushik Parthasarathi, Hideo Ichimura, Eiji Monma, Jens Lindert, Sadiqa Quadri, Andrew Issekutz, Jahar Bhattacharya

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Figure 1

Photolytic uncaging-induced Ca2+ responses in rat lung capillaries.

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                  Photolytic uncaging-induced Ca2+
                  re...
(A) Fluorescence images in pseudocolor of a rat capillary network loaded with fluo-4 and NP-EGTA show endothelial Ca2+ level at baseline (left) and after Ca2+ uncaging (right). Dashed lines and circle in baseline image represent capillary margins and uncaging target, respectively. Arrowheads indicate measurement sites on venules. The distance between measurement and uncaging sites was determined along the vascular length (dotted line). (B) Tracings show temporal decay of endothelial Ca2+ level at the uncaging site (black) and in a responding venule (red). (C) Filled circles represent mean Ca2+ responses (± SEM) to uncaging at indicated distances from the uncaging site. Each mean was higher than the baseline endothelial Ca2+ value (79 ± 10 nM). Line calculated by exponential regression of means (r2 = 0.99). Values predicted by a computational model of diffusion (open triangles) were not significantly different from experimental values. The dashed line indicates 50% of initial. *P < 0.05 compared with baseline. (D) Tracings show responses to repeated uncaging in a capillary. As indicated, NP-EGTA was loaded after the first response (no. 1). Response nos. 1–3 were obtained at the same capillary site. Response no. 4 was obtained at a different site. The experiment was replicated 3 times. (E) Plot of fluo-4 fluorescence intensity against Ca2+ concentration determined at identical endothelial locations. Solid line calculated by linear regression (r2 = 0.42). Dashed lines indicate 95% confidence intervals. Data are from 5 capillaries coloaded with fluo-4 and fura-2.
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