Reply to Mehmood: Adrenomedullin: A Double-edged Sword in Septic Shock and Heart Failure Therapeutics?

From the Author:

I thank Dr. Mehmood for his comments. I agree that the pathological importance of vascular leakage extends far beyond sepsis and acute lung injury (acute respiratory distress syndrome) to include diverse syndromes such as heart failure (1, 2), renal failure (3), and connective tissue diseases (4). In my opinion, this reflects the fact that increased endothelial permeability is usually maladaptive, given the detrimental effects of tissue edema. Furthermore, severe vascular leakage may be difficult for the body to remediate, given the limited ability of the mature endothelium to proliferate (5).

As we enter the era of clinical trials for agents that stabilize the vascular barrier (6), it is important to remember that multiple cellular and molecular mechanisms exist for vascular leakage. These include endothelial apoptosis (7), pyroptosis (8), and remodelling of endothelial cell–cell junctions and the cellular cytoskeleton (9). The success of drugs aimed at reducing vascular leakage in clinical trials may therefore depend on the cause of the leakage and the mechanism of action of the drug. Nonetheless, given its ubiquity in clinical medicine, the prospect of either harnessing (10) or counteracting vascular leakage without impairing the immune response (11) is an intriguing prospect for clinicians.