This is consistent with earlier studies showing that agonists activating adenylyl cyclase can antagonize thrombin-induced hyperpermeability (4). IMD-mediated barrier protection was abolished by a peptide SB203580 p38 MAPK inhibitor antagonist of CRLR, which clearly demonstrates that IMD produces its effects via CRLRs. Together these data suggest that IMD protects endothelial barrier function against imminent failure via activation of PKA pathway involving CRLR. The barrier-protective effect of IMD is further supported by our data obtained in an isolated, buffer-perfused lung model in which IMD substantially decreased pressure-induced endothelial permeability as measured by the alteration of Kfc. The effect of IMD on endothelial permeability matched that of DBcAMP, consistent with the concept that IMD acts on endothelial cells via the CRLR signaling cascade with stimulation of adenylyl cyclase and cAMP synthesis.

In the lung, hypoxia is closely associated with a fall in intracellular cAMP levels (38) and results in suppression of epi- and endothelial barrier function, leading to pulmonary edema (12, 45). Since IMD is upregulated by hypoxia and exerts profound stabilizing effects on endothelial barrier function both in cell culture and in the isolated, perfused lung, it might be part of a protective regulatory mechanism counteracting hypoxia-induced pulmonary edema. In conclusion, the present data indicate a pivotal role of IMD in the regulation of endothelial cell function in the pulmonary microvasculature, where IMD is upregulated by hypoxia and serves as a stabilizer of endothelial permeability.

This may be critical for improved treatment of patients with disturbances of this vascular segment as they occur in high-altitude pulmonary edema, acute respiratory distress syndrome, and sepsis. GRANTS This work was supported by the Deutsche Forschungsgemeinschaft (SFB 547, projects A3, B7, and C1; Excellence Cluster Cardiopulmonary System) and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-70652 (S. Y. T. Hsu). ACKNOWLEDGMENTS The skillful technical assistance of K. Michael is greatly appreciated.
Enterohaemorrhagic Escherichia coli (EHEC) strains such as O157:H7 are important human food-borne pathogens [1], [2]. EHEC and Shigella dysenteriae infect more than 150 million people each year and cause more than a million deaths [3].

EHEC causes a variety of symptoms from watery diarrhea to hemorrhagic colitis, and severe complications such as haemolytic-uraemic Anacetrapib syndrome (HUS) that can cause death in up to 5% of HUS cases [4], [5]. There is no effective treatment because large amounts of Shiga toxins (Stx), virulence factors produced by EHEC, are released from EHEC on treatment with antibiotics [4], [6]. Two types of Stx, Stx1 and Stx2, are known to be associated with human diseases [7], [8].