Allergic lung inflammation induces pulmonary vascular hyperresponsiveness.
Pulmonary arterial vasoconstriction is an important early component of pulmonary hypertension. Inflammatory mechanisms play a prominent role in the pathogenesis of pulmonary hypertension. The present authors investigated the potential role of acute allergic lung inflammation for alterations in pulmonary haemodynamics. BALB/c mice were intraperitoneally sensitised to ovalbumin and challenged by ovalbumin inhalation. Subsequently, lungs were ventilated and perfused ex vivo, and pulmonary arterial pressure (P(pa)) was continuously monitored. Isolated perfused lungs of allergen-sensitised and -challenged mice showed five-fold enhanced P(pa) responses to serotonin, which is reported to be a significant contributor to pulmonary hypertension in humans. This increase in P(pa) was abolished by the serotonin receptor-2A antagonist ketanserin, but not the serotonin receptor-1B antagonist GR127935. Intracellular signalling to serotonin involved phosphatidylcholine-specific phospholipase C and protein kinase C, as well as Rho-kinase, as assessed by employing the specific inhibitors D609, bisindolylmaleimide and Y27632, respectively. In addition to serotonin, impressively enhanced P(pa) increases in allergic lungs were also evoked by the thromboxane receptor agonist U46619, angiotensin II and endothelin-1. In conclusion, allergic lung inflammation was accompanied by impressive pulmonary vascular hyperresponsiveness. These results suggest a possible role for allergic inflammation in the development of pulmonary arterial hypertension.
Dept of Internal Medicine, Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Schumannstr 20/21, 10117 Berlin, Germany. martin.witzenrath@charite.de
M
M
Witzenrath
B
B
Ahrens
S M
SM
Kube
A C
AC
Hocke
S
S
Rosseau
E
E
Hamelmann
N
N
Suttorp
H
H
Schütte
D000818:Animals; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011652:Pulmonary Circulation; D015398:Signal Transduction; D014661:Vasoconstriction