Angiotensin II May Enhance Bacterial Clearance in Clinical Sepsis

Matthew D. Taylor, MD, provides insight into the potential effects of angiotensin II on bacterial clearance and the systemic inflammatory response in clinical sepsis.
Angiotensin II was associated with enhanced bacterial clearance in a murine model of sepsis, suggesting it may augment immune responses in clinical sepsis.

Angiotensin II was found to be associated with an increase in the myeloid innate immune response during severe systemic infection, suggesting angiotensin II may improve immune responses in the setting of clinical sepsis. These study findings were published in PNAS.1

Researchers conducted a study to determine whether angiotensin II augments the immune response using a murine cecal ligation and puncture (CLP) model of sepsis, an animal model designed to demonstrate some features of sepsis in humans. To assess the effects of angiotensin II on the immune response to CLP, the researchers randomly assigned 4 cohorts of mice to 4 different treatments. These treatments included intraperitoneal angiotensin II alone, intraperitoneal angiotensin II plus losartan, subcutaneous angiotensin II, or vehicle.

Results showed that treatment with angiotensin II was associated with increased bacterial clearance from the blood and the peritoneal cavity, as well as a modified host immune response, following CLP. Of note, these effects were not observed among a subset of mice treated within norepinephrine.

Further analysis showed that the effects of angiotensin II treatment on bacteremia burden following CLP were negated by selective angiotensin type 1 receptor (AT1R) deletion in myeloid-lineage leukocytes. Similar results were observed when angiotensin II was co-administered with losartan, suggesting that the effects of angiotensin II on bacteremia burden are mediated via AT1R.

According to the researchers, “Early and effective source-control is a critical element of resuscitation for sepsis.” They also noted, “An effect of angiotensin-II to promote pathogen clearance could have broad clinical implications.”

Limitations include the short follow-up period, the use of a CLP murine model, and the extrapolation of rodent immunology to human disease.

“[T]hese findings suggest the immunomodulatory properties of angiotensin-II warrant further exploration in clinical sepsis,” the researchers concluded.

To elaborate on these findings, we spoke with Matthew D. Taylor, MD. Dr Taylor is an Instructor at the Institute of Molecular Medicine at the Feinstein Institutes, as well as an Assistant Professor of Pediatric Critical Care Medicine in the Pediatrics Division of Zucker School of Medicine at Hofstra University and Northwell Health.

Angiotensin II treatment led to a greater increase in bacterial clearance compared with norepinephrine, indicating its high value in the setting of clinical sepsis. Can you elaborate on the exact mechanism that allows this increase in bacterial clearance?

Dr Taylor: We found that angiotensin II increased white blood cell (specifically neutrophil and monocyte) trafficking toward the source of angiotensin II. In our model, where that source was in the peritoneum, those white blood cells were able to clear bacteria more quickly than that which occurred in the absence of angiotensin II. We do not believe norepinephrine has this effect. Angiotensin II also increases the ability of white blood cells to kill bacteria through phagocytosis.

If put into practice in human patients, are there any patient-specific risk factors or considerations clinicians should be aware of if angiotensin II treatment were to be administered to a patient undergoing septic shock?

Dr Taylor: It is too soon to say which patients might benefit from the immune effects of angiotensin II in sepsis. Importantly, angiotensin II is Food and Drug Administration (FDA)-approved to treat hypotension of the type that often accompanies sepsis. There are theoretical reasons as to why angiotensin II might be preferable to norepinephrine — the current first-line drug — that include but are not limited to its associated immune effects. Further studies that can identify patients who may benefit from angiotensin II are still needed. 

These study results suggest that both systemic angiotensin II and myeloid leukocyte-bound angiotensin converting enzyme (ACE)-1 promote protection against pathogens via distinct mechanisms. Can you elaborate further on this protective mechanism in regard to myeloid leukocyte-bound ACE-1 and the possible ways in which these data can be implemented into clinical practice?

Dr Taylor: Angiotensinogen is made by the liver and forms angiotensin I in the blood. ACE-1 converts angiotensin I to angiotensin II. Angiotensin II acts on a number of different angiotensin receptors. Our study focused on 1 specific receptor, AT1R.  A number of ACE-1 inhibitors are commonly used to treat hypertension. It is intriguing to speculate whether ACE-1 inhibitors, such as enalapril, or angiotensin II receptor antagonists like losartan, could modulate innate immunity and affect the response to infection or sepsis. Findings from large studies among patients with sepsis receiving ACE-1 inhibitors or angiotensin inhibitors have not identified any differences, but individual patients may in some way be affected by these drugs.

An effect of angiotensin-II to promote pathogen clearance could have broad clinical implications.

What are some of the possible advantages and disadvantages of angiotensin II treatment vs norepinephrine for a patient with clinical sepsis? 

Dr Taylor: Our work demonstrates that angiotensin II augmented the immune response in our mouse model of sepsis. We did not see this response with norepinephrine. Although this may translate to patients with clinical sepsis, our understanding of the immune response to sepsis is incomplete. It is possible that some patients may need an increased immune response to fight infection, but others may actually be harmed by an increased immune response.

Further research is necessary to understand this balance and to understand which patients may benefit from angiotensin II treatment. We previously found that treatment with angiotensin II may improve kidney function in sepsis-associated acute kidney injury in our model.2 We also previously noted that angiotensin II treatment seemed to be effective in improving kidney function and disease severity in a small cohort of patients with COVID-19-related septic shock compared with patients who received standard care.3 Much of this requires further study to truly understand the effects of angiotensin II on sepsis and septic shock, but we believe that our studies support these pursuits.

Where do you believe future research efforts should be directed to improve outcomes related with pathogen clearance in septic shock?

Dr Taylor: I believe that we have to have a better understanding of the immune response to sepsis. The immune modulating drugs that are widely used in rheumatologic or oncologic processes cannot be safely used to treat sepsis because we do not understand what the immune system is doing in sepsis nor what sepsis is doing to the immune system. Our laboratory is trying to understand 2 areas that we believe significantly impact sepsis immunology:

  • How angiotensin II deficiency or signaling resistance may blunt the sepsis immune response in both innate immunity and in adaptive T-cell immunity; and
  • How T-cell memory responses that occur because of prior infections over the lifetime of a patient with sepsis may impact the immune response after the onset of sepsis.

These 2 areas are vitally important in understanding how we can modify immune responses to treat sepsis and help our patients survive a stay in the intensive care unit and avoid some of the long-term problems that plague sepsis survivors.

References:

1. Leisman DE, Privratsky JR, Lehman JR, et al. Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model. Proc Natl Acad Sci USA. Published online August 15, 2022. doi:10.1073/pnas.2211370119

2. Leisman DE, Fernandes TD, Bijol V, et al. Impaired angiotensin II type 1 receptor signaling contributes to sepsis-induced acute kidney injury. Kidney Int. 2021;99(1):148-160. doi:10.1016/j.kint.2020.07.047

3. Leisman DE, Mastroianni F, Fisler G, et al. Physiologic response to angiotensin II treatment for coronavirus disease 2019-induced vasodilatory shock: a retrospective matched cohort study. Crit Care Explor. Published online September 29, 2020. doi:10.1097/CCE.0000000000000230