Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries.
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 microm 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.
Parthasarathi
Kaushik
K
Lung Biology Laboratory, St. Luke's-Roosevelt Hospital Center, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10019, USA. kp257@columbia.edu
Ichimura
Hideo
H
Monma
Eiji
E
Lindert
Jens
J
Quadri
Sadiqa
S
Issekutz
Andrew
A
Bhattacharya
Jahar
J
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002196:Capillaries / Q000503:physiopathology*; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D008168:Lung / Q000503:physiopathology*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D010782:Photolysis; D011652:Pulmonary Circulation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018031:Connexin 43; D010455:Peptides; D002118:Calcium