Protecting endothelial function in septic patients: a hopeful strategy?

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The damage and dysfunction of vascular endothelial cells (ECs) are the shared characteristics in systemic reactions caused by sepsis. During sepsis, microbial pathogens can cause damage to vascular ECs, resulting in a series of adverse consequences, including excessive inflammatory responses, microvascular leakage, decreased vascular tone, and microthrombus formation. Lots of research have reported the progress on factors and mechanisms that may affect the permeability and regulated cell death (RCD) of ECs under septic conditions, including glycocalyx, damage-associated molecular patterns, and various forms of RCD in ECs, such as apoptosis, proptosis, ferroptosis, and autophagy. However, this current research predominantly relies on animal studies, which have inherent limitations. Translating experimental findings from animal models to clinical practice has been highly challenging. Bestle et al1 published a randomized controlled double-blind clinical trial in which they investigated the efficacy and safety of low-dose iloprost as an endothelial function-protecting agent on organ function in septic shock patients with endothelial injury. The results showed that Sequential Organ Failure Assessment (SOFA) scores, 90-day SOFA scores, and 28-day mortality rates in patients receiving iloprost were not statistically different from the saline group. Obviously, as a clinical therapy targeting endothelial function, it is a very disappointed result for all researchers who are concerned with endothelial function during sepsis. Iloprost is a synthetic analogue of prostacyclin PGI2, which has been demonstrated to dilate both systemic and pulmonary arterial vascular beds, inhibit platelet aggregation, and is currently used in the treatment of pulmonary hypertension.2 The role of iloprost in inhibiting platelet aggregation can not be ignored. It has been demonstrated that activated platelets can stimulate the inflammatory pathways, oxidative stress, and apoptosis, leading to a deleterious impact on endothelial cells, even endothelial dysfunction,3 which is a pivotal factor in the pathogenesis of kidney injury.4 And the interactions between platelets and endothelial cells lead to small-vessel thrombosis, when inhibited platelet activation was able to effectively reduce endothelial injury and microvascular thrombosis.5 It is clear that iloprost can play a role in protecting endothelial function through antiplatelets. Bestle’s team has demonstrated that small doses of iloprost have no effect on platelet function, so they chose a small dose of iloprost to try to find evidence of protective endothelial function in the nonplatelet pathway, but failed in the final results. However, which is not surprising for sepsis is a systemic disease involving inflammation, immunity, coagulation, and other systems, it is very difficult to exclude the interference of other factors. Even if iloprost does protect endothelial cell function, it is very likely that other systemic dysfunctions may mask this fact. So it may be easier to get positive results in cellular or animal experiments to study small doses of iloprost. It is also worth thinking about the appropriateness of choosing SOFA as an outcome indicator in this study. Although sepsis 3.0 clarifies that it is organ function damage that leads to the death of patients,6 we must not neglect the fact that organ function damage is predicated on the dysregulated response of the organism to infection. Organ dysfunction represents the ultimate adverse consequence of infection, emerging because of an intricate network of organismal responses. The pathway from the initial intervention in endothelial cell function, a point within the body’s response network, to the subsequent assessment of changes in organ function is too remote to be readily discernible. Therefore, although preservation of organ function is the objective of sepsis treatment, it may have been more feasible to achieve favorable outcomes by selecting indicators that are more closely aligned with endothelial cell function. Our team believes the stress response is the body’s protective response to infection. Furthermore, it is also the key determinant of whether the disease progresses further or is controlled, as sepsis 3.0 identifies the host’s dysregulated response as an important pathway for infections that lead to multiple organ dysfunction syndrome. We categorized the host’s dysregulated response into three parts: neurological and neuroendocrine responses, endothelial activation-related performance (e.g., inflammatory, immune, and coagulation responses), and metabolic and bioenergetic responses. These three components interact with each other and collectively determine the onset and progression of sepsis. It is evident that although the role of endothelial activation in the pathophysiological process of sepsis is well established, focusing on endothelial function alone is an inadequate approach to the treatment of sepsis. Locating key sites that cut across all organismal responses may be a promising avenue for overcoming the challenge of sepsis treatment. There have been no significant advances or breakthroughs in the treatment of sepsis, and numerous studies on the pathophysiologic mechanisms of sepsis have not been validated in clinical patients. Among them, endothelial damage is a recognized pathophysiological mechanism, and because the endothelium exists in every blood vessel in the body, many researchers even define sepsis as a kind of “endothelial disease,” which emphasizes the unshakeable position of endothelial function during sepsis. Nevertheless, previous studies have also identified numerous additional mechanisms (in cellular and animal studies) that influence the development of sepsis, in addition to endothelial activation. It is necessary to consider whether endothelial activation is as pivotal as previously speculated and whether interventions of endothelial function can effectively address the treatment dilemma of sepsis. This is not intended to discourage further research into sepsis but rather to expect a more open and comprehensive approach in future studies. Acknowledgements None. Conflicts of interest The authors declare that they have no conflicts of interest with regard to the content of this report.

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