1. Introduction

Our focus in the following is on the potential of aquaporins modulators as a novel approach to treating sepsis; a discussion of the full spectrum of aquaporins’ implications for health and disease is beyond the scope of this report.

The intersection of sepsis and aquaporins

Sepsis, a life-threatening syndrome caused by organ failure after infection, is one of the leading causes of mortality worldwide. It is estimated to cause 5.3 million global deaths annually.¹ It is also one of the most expensive medical conditions to treat, since many of the severe cases must be treated in ICU wards.² In the context of contemporary medical challenges such as emerging viral infections, increased older population and co-morbidities, and reduced post-surgery staying days in hospitals, the threat from sepsis is growing bigger.

Traditionally, the three cornerstones of sepsis treatment have been infection source control, antibiotic therapy, and organ support. These treatments are more supportive in nature. There is no specific medicine targeting sepsis. With the increasing challenges we face, these treatments clearly are not sufficient. In the past few decades, numerous drug candidates have been developed and tested as potential adjunct therapies. Unfortunately, almost none of them have shown any survival benefit.³ Consequently, the development of new sepsis drugs has markedly decreased in recent years. New approaches to the old problem of treating sepsis syndrome are urgently needed.

As our knowledge of sepsis pathophysiology and pathway expands, various phenotypes have been characterized instead of just one single sepsis profile. This has created the prospect of identifying multiple targets for new drugs, with those targeting dysregulated immune response being the most promising.⁴

Aquaporins (AQPs) are transmembrane channel proteins that mainly facilitate the transport of water across cells. The discovery of AQP in 1992 won Peter Agre a Novel Prize and opened doors for new fundamental scientific insights and promising therapeutic approaches to many health conditions. Nearly 30 years after the discovery of AQPs, they remain elusive as potential drug targets despite being present in many human tissues and organs and involved in many physiological functions.

However, there have been many developments and breakthroughs in finding AQP modulators and understanding their roles in health and disease. A few AQP-based therapies have either entered clinical trials or are just at the doorstep.

In looking into the mechanism of AQPs and its potential application in sepsis and summarizing the present discoveries and the outlook for sepsis management, Supertrends explores how the two trends are interacting and discusses their possible impact on society. We hope that this overview can help to answer some of the crucial questions in healthcare that we are facing today.

Executive Summary

Sepsis is a highly heterogeneous and complex syndrome initiated by infection and characterized by organ dysfunction with variable progression and outcome. Genetic predisposition has also been found to play a role. The pathophysiology of sepsis involves both pro-inflammatory and anti-inflammatory responses from the host. Sepsis management can be subdivided into two parts – immediate infection control and cardiorespiratory resuscitation in the first six hours, followed by organ function support. So far, there is no specific adjunct therapy targeting sepsis.

AQPs are a family of membrane water channel proteins that osmotically modulate water fluid homeostasis in several tissues; some of them also transport small solutes such as glycerol. The human body expresses 13 AQPs with specific organ, tissue, and cellular localization. AQPs are involved in a wide range of physiological functions. In general, AQPs play a role in maintaining homeostasis of water levels and many other physiological processes. There is great promise in the development of small-molecule AQP modulators for clinical applications, including treatment of sepsis and cytokine storms, refractory oedema, cancer, glaucoma, certain brain conditions, obesity, etc.

Today, we are facing new challenges in healthcare, such as emerging viral infections, in a population that increasingly suffers from old age and co-morbidities. In this situation, the threat from sepsis shows new characteristics and has gained new urgency. AQP-based therapy, together with a personalized approach, may help scientists find a specific treatment for the dysregulated immune response in sepsis.

Aquaporins: Transmembrane proteins that form pores across cellular membranes. They facilitate the transport of water and other molecules such as glycerol into or out of cells.

Cytokine storm: “Cytokines are small proteins released by many different cells in the body, including those of the immune system where they coordinate the body’s response against infection and trigger inflammation. The name ‘cytokine’ is derived from the Greek words for cell (cyto) and movement (kinos).”⁶A cytokine storm is a “severe immune reaction in which the body releases too many cytokines into the blood too quickly.” “Sometimes, a cytokine storm may be severe or life threatening and lead to multiple organ failure.”⁷ “Cytokine storms can be caused by a number of infectious and non-infectious etiologies, especially viral respiratory infections such as H5N1 influenza, SARS-CoV-1, and SARS-CoV-2 (COVID-19 agent).”⁸

Glaucoma: is a disease of increased pressure in your eyes that eventually can damage your eye’s optic nerve. It usually happens when fluid builds up in the front part of your eye.¹⁰

Oedema: excess fluid that build up in the body’s tissue. Oedema causes swelling in the body.⁹

Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response to infection.⁵

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8. Wikipedia, “cytokine storm”. https://en.wikipedia.org/wiki/Cytokine_storm. Accessed January 2021.

9. Marie Curie. https://www.mariecurie.org.uk/help/support/terminal-illness/manage-symptoms/fluid-build-up-oedema. Accessed January 2021.

10. Boyd, K. 2020. What is glaucoma? American Academy of Ophthalmology https://www.aao.org/eye-health/diseases/what-is-glaucoma