Acute chest syndrome (ACS), a life-threatening complication, can arise from sickle cell disease; however, the precise mechanisms underlying this condition remain elusive.
A recent study conducted by investigators at Mass General Brigham has pinpointed an ancient immune pathway that is activated during ACS in patients and plays a pivotal role in driving the disease. By blocking this pathway with existing medications, researchers mitigated disease severity in preclinical models. These findings have been published in Science Translational Medicine.
Science Translational Medicine"Although ACS remains the primary cause of mortality among sickle cell disease patients, our current options are restricted to supportive care," said corresponding author Sean Stowell, MD, Ph.D., from the Department of Pathology at Brigham and Women's Hospital. "Our research unveils potential targets for therapeutic intervention, addressing this devastating condition."
Sickle cell disease is caused by a mutated form of hemoglobin that initiates red blood cell destruction (hemolysis). This can result in blocked blood vessels, lung injuries, eventually leading to ACS—a condition with symptoms such as shortness of breath, chest pain, and wheezing which can rapidly worsen and become fatal.
Previous research has suggested that hemolysis activates the complement system, a sequence of immune proteins designed to combat pathogens. However, how the complement system contributes to ACS progression was unclear.
The study team analyzed blood samples from 27 sickle cell disease patients and found higher baseline levels of complement activation compared to healthy controls. Activation was also increased in those experiencing ACS episodes. Using a mouse model with sickle cell disease, investigators noted that the complement pathway assisted in breaking down red blood cells, indicating factors outside mutated RBCs contribute to sickle cell symptoms.
Moreover, they discovered that complement-driven breakdown of red blood cells triggers a cycle leading to further complement activation and ACS development. By targeting or blocking certain complement proteins with existing drugs, researchers reduced the destruction of red blood cells and prevented ACS in their animal studies.
The authors suggest conducting randomized clinical trials to determine if complement inhibitors could effectively treat ACS patients.