A chemotherapy drug widely used in ovarian, lung, stomach, and other cancers, may cause heart toxicity that can lead to congestive heart failure, a study led by an Indian-origin researcher warns.
Researchers from the University of Alabama at Birmingham (UAB) in the US found that the drug doxorubicin disrupts metabolism that controls immune responses in the spleen and heart.
These immune responses are vital for heart maintenance, repair and control of inflammation, according to the research published in the American Journal of Physiology - Heart and Circulatory Physiology.
This dysregulated immunometabolism impairs resolution of inflammation, and chronic, non-resolving inflammation leads to advanced heart failure.
Immunometabolism is the study of how metabolism regulates immune cell function, and it is a recent and growing aspect of immunology.
Two key players in immunometabolism are immune-responsive enzymes called lipoxygenases and cyclooxygenases.
These immune-sensitive enzymes create a variety of bioactive lipid mediators that regulate immune cell responses.
The researchers, led by Ganesh Halade, an assistant professor at UAB, used a mouse model to study the effect of doxorubicin on immunometabolism.
In the mice, doxorubicin induced fibrosis in the heart, increased the programmed cell death called apoptosis and impaired the pumping of the heart.
The drug also caused a wasting syndrome in the heart and the spleen, researchers said.
Mounting research has shown that the spleen - which acts as a reservoir of immune cells that speed to the site of heart injury to begin clearance of damaged tissue - plays a leading role in the initiation of immune response after a heart attack.
Now, Halade and colleagues have found that the doxorubicin is also involved in the deleterious response to the spleen.
First, the researchers found that doxorubicin induced irreversible dysregulation that lowered levels of lipoxygenases and cyclooxygenases in the left ventricle of the heart.
This reduced the levels of bioactive lipids mediators produced by these enzymes, mediators that usually would help resolve inflammation.
Second, in the spleen, doxorubicin also poisoned a special group of marginal zone immune cells called CD169+ macrophages, causing the spleen to diminish in size.
Third, doxorubicin caused an imbalance of the cell-signaling molecules called chemokines and cytokines, and this imbalance suggests suppressed defense capacity of spleen-leukocyte immune cells....