Krishnan Lab

The lab of Mohan Krishnan, PhD, investigates the pathophysiology of transfusion-associated necrotizing enterocolitis, systemic inflammatory response syndrome and neurodevelopmental deficits in premature infants who are at high risk of anemia and are heavily transfused.

The lab's main goal is to understand the role of monocyte/macrophages in the neonate and investigate their inflammatory phenotype and function during anemia and during the conditions of necrotizing enterocolitis, systemic inflammatory response syndrome and neurodevelopmental deficits when associated with red blood cell transfusion.

Current Projects

Transfusion-associated Necrotizing Enterocolitis

Prior to the development of the Krishnan lab's innovative murine model of transfusion-associated necrotizing enterocolitis, the collective understanding of this disease process was largely limited to retrospective case-control studies. The lab's model directly addresses inconsistencies and controversies brought up by earlier investigations that incompletely characterized transfusion-associated necrotizing enterocolitis at the cellular level, particularly concerning the amount of inflammatory injury attributed to preceding anemia versus resultant transfusion.

The association between red blood cell transfusion and necrotizing enterocolitis finds biological plausibility in observations of altered splanchnic autoregulation following red blood cell transfusions, but several systematic reviews and meta-analyses of such observational data have offered inconsistent conclusions.

The lab's model demonstrates a two-hit mechanism, whereby severe anemia creates a low-grade inflammatory state in the intestinal mucosa characterized by macrophage recruitment, and subsequent red blood cell transfusions activate these macrophages via a toll-like receptor-4-mediated mechanism to infiltrate and causenecrotizing enterocolitis-like injury. The risk and severity of intestinal injury directly correlate with the severity and duration of anemia prior to transfusion.

Notably, this is the first and only animal model ever developed to investigate this phenomenon and finally provides mechanistic insights into the association of blood transfusions and necrotizing enterocolitis that had been identified in more than 30 clinical studies. With support from the NIH, this model has resulted in four first-authored manuscripts, including the Krishnan lab's seminal publication in Nature Communications. Projecting forward, this model provides the groundwork to understand the mechanisms by which necrotizing enterocolitis-like injury can be ameliorated, as the lab pilots targeted novel anti-inflammatory therapies.

Transfusion-associated Systemic Inflammatory Response Syndrome 

Transfusions of red blood cells are necessary and lifesaving in premature and critically ill infants, who experience severe anemia due to both physiologic and iatrogenic factors. In recent years, the Krishnan lab and others have shown that severe anemia was associated with increased intestinal permeability, demonstrated by the identification of endotoxin in the bloodstream. Additionally, there is increasing recognition of the dangers of the necessary step of blood bank storage prior to transfusion.

Transfusions of stored red blood cells are rapidly cleared by liver macrophages, producing non-transferrin-bound iron to circulate in plasma, acutely inducing inflammation through iron deposition in tissues. The risks of experiencing severe anemia during critical developmental periods must be balanced with the risks of transfusions, which can lead to systemic inflammatory response syndrome and potentially multi-organ dysfunction syndrome. The lab is investigating the mechanisms of systemic inflammatory response syndrome reated to red blood cell transfusions in neonatal severe anemia, which is a critical step in the development of effective therapeutic strategies to prevent the development of multi-organ dysfunction syndrome in these neonates.

Anemia and Red Blood Cell Transfusion-associated Brain Inflammation and Neurodevelopmental Deficits

Preterm neonates comprise one of the most heavily transfused populations, as 50-94% of very low birth weight infants receive at least one red blood cell transfusion during their stay in the neonatal intensive care unit to correct anemia, which is associated with increased morbidity and mortality worldwide.  The Krishnan lab's high-caliber murine model also sets the foundation for rigorous evaluations of transfusion-associated necrotizing enterocolitis and its effects on impairment of neurodevelopment in adults, particularly concerning immunological changes in the brain that predispose to neuroinflammation.

The lab recently identified that anemic and anemic transfused murine neonates have impaired cognition in adulthood. Now we are extending these observations and investigating the role of anemia and red blood cell transfusion on brain inflammation/injury, which will be critical for improving the strategies for clinical practice and developing targeted interventions to ameliorate transfusion-related neurodevelopmental deficits.