Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Abstract

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB's role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.

Keywords: Sepsis; blood-brain barrier; drug delivery; neuroinflammation; sepsis-associated encephalopathy; tissue non-specific alkaline phosphatase.

Figure 1.

Comparison of the past and present guidelines for diagnosis of sepsis and septic shock. (A) Past guidelines stressed that the diagnosis and progression of sepsis from a systemic inflammatory response to multiple organ dysfunction was sequential rather than multifactorial. (B) The current guidelines for defining sepsis and septic shock stress that multiple linked considerations are necessary for an accurate diagnosis. Both the past and present guidelines involve a clinical screening tool for patients likely to have sepsis that includes a clinical characterization of the severity of the disease. Clinicians have traditionally used a Sequential Organ Failure Assessment (SOFA) system to categorize the severity of organ dysfunction in sepsis, which associates a higher SOFA score with increased mortality.^, New sepsis guidelines employ a quick Sequential Organ Failure Assessment (qSOFA) score, which is a modified version of the SOFA score that includes altered mental status, a systolic blood pressure ⩽ 100 mm Hg, and a respiratory rate ⩾ 22/min. Patients with a qSOFA score ⩾ 2 have an overall in-hospital mortality risk greater than 10%.^, If warranted, further clinical analysis can be completed using other SOFA criteria. Source: Adapted from Singer et al.

Figure 2.

Complex neuroinflammatory processes promote BBB dysfunction in early sepsis which enhance neuronal dysfunction and trigger cognitive impairment. Highly complex and multifactorial mechanisms transduce systemic inflammatory signals to the brain in early sepsis, resulting in neuronal dysfunction and subsequent acute and chronic cognitive impairment. The BBB serves as both a nexus and an interface for these signals. Sepsis begins with systemic infection that evokes an exaggerated host immune response from the recognition of pathogen-associated molecular patterns (PAMPs). In this example, sepsis is triggered by a local lung infection (eg, pneumonia). Systemic proliferation of the infection initiates a hyperinflammatory response that stimulates the production of immune cells, cytokines, and other inflammatory mediators. These inflammatory mediators initiate a cascade of events that either directly or indirectly impact the peripheral microcirculation via cardiovascular autonomic alterations, or activation of the coagulation cascade, and converge on cerebral microvessels and their component BBB endothelial cells. Cerebral hypotension and microthrombus formation also initiate ischemia. The convergence of these events lead to BBB dysfunction, including immune cell infiltration, upregulation of adhesion molecules, increased BBB permeability, activation of cerebral cytokines, cerebral edema, and enhanced neuroinflammation.^,,, Positive feedback of the disrupted BBB on neuroinflammation and potential amplification of this feedback is indicated by the solid bidirectional arrow (direct feedback) and the dotted arrow (indirect feedback). BBB, blood-brain barrier; CP, choroid plexus; CVOs, circumventricular organs; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; NO, nitric oxide.

Figure 3.

Alkaline phosphatase (AP) activity in the brain and BBB. (A) Histological staining for AP activity shows decreased TNAP enzyme activity in the cortex of septic male mice (10-15 months old) subjected to the cecal ligation and puncture (CLP) model of experimental sepsis. C57BL/6J mice were subjected to CLP or a sham injury and brains were harvested 24 hours later. (B) Graph shows the quantification of cortical AP enzyme activity in CLP (n = 3, 52.49 ± 0.1094) versus sham (n = 3, 53 ± 0.1142) mice (sections = 3 per mouse; data represented as mean ± SEM, *P < .05, t(4) = 3.384, unpaired Student’s t-test, scale bar = 115 µm). AP activity was assessed in 35-µm brain sections with the BCIP/NBT AP Substrate Kit (Vector Laboratories, Burlingame, CA) following previously published methods. BBB, blood-brain barrier; TNAP, tissue non-specific alkaline phosphatase.