Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts.

Leukocytes normally marginate toward the vascular wall in large vessels and within the microvasculature. Reversal of this process, leukocyte demargination, leads to substantial increases in the clinical white blood cell and granulocyte count and is a well-documented effect of glucocorticoid and catecholamine hormones, although the underlying mechanisms remain unclear. Here we show that alterations in granulocyte mechanical properties are the driving force behind glucocorticoid- and catecholamine-induced demargination. First, we found that the proportions of granulocytes from healthy human subjects that traversed and demarginated from microfluidic models of capillary beds and veins, respectively, increased after the subjects ingested glucocorticoids. Also, we show that glucocorticoid and catecholamine exposure reorganizes cellular cortical actin, significantly reducing granulocyte stiffness, as measured with atomic force microscopy. Furthermore, using simple kinetic theory computational modeling, we found that this reduction in stiffness alone is sufficient to cause granulocyte demargination. Taken together, our findings reveal a biomechanical answer to an old hematologic question regarding how glucocorticoids and catecholamines cause leukocyte demargination. In addition, in a broader sense, we have discovered a temporally and energetically efficient mechanism in which the innate immune system can simply alter leukocyte stiffness to fine tune margination/demargination and therefore leukocyte trafficking in general. These observations have broad clinically relevant implications for the inflammatory process overall as well as hematopoietic stem cell mobilization and homing.

Neutrophil Migratory Patterns: Implications for Cardiovascular Disease.

The body's inflammatory response involves a series of processes that are necessary for the immune system to mitigate threats from invading pathogens. Leukocyte migration is a crucial process in both homeostatic and inflammatory states. The mechanisms involved in immune cell recruitment to the site of inflammation are numerous and require several cascades and cues of activation. Immune cells have multiple origins and can be recruited from primary and secondary lymphoid, as well as reservoir organs within the body to generate an immune response to certain stimuli. However, no matter the origin, an important aspect of any inflammatory response is the web of networks that facilitates immune cell trafficking. The vasculature is an important organ for this trafficking, especially during an inflammatory response, mainly because it allows cells to migrate towards the source of insult/injury and serves as a reservoir for leukocytes and granulocytes under steady state conditions. One of the most active and vital leukocytes in the immune system's arsenal are neutrophils. Neutrophils exist under two forms in the vasculature: a marginated pool that is attached to the vessel walls, and a demarginated pool that freely circulates within the blood stream. In this review, we seek to present the current consensus on the mechanisms involved in leukocyte margination and demargination, with a focus on the role of neutrophil migration patterns during physio-pathological conditions, in particular diabetes and cardiovascular disease.

Hiding in plain sight? A review of post-convulsive leukocyte elevations.

During physiological stress responses such as vigorous exercise, emotional states of fear and rage, and asphyxia, the nervous system induces a massive release of systemic catecholamines that prepares the body for survival by increasing cardiac output and redirecting blood flow from non-essential organs into the cardiopulmonary circulation. A curious byproduct of this vital response is a sudden, transient, and redistributive leukocytosis provoked mostly by the resultant shear forces exerted by rapid blood flow on marginated leukocytes. Generalized convulsive seizures, too, result in catecholamine surges accompanied by similar leukocytoses, the magnitude of which appears to be rooted in semiological factors such as convulsive duration and intensity. This manuscript reviews the history, kinetics, physiology, and clinical significance of post-convulsive leukocyte elevations and discusses their clinical utility, including a proposed role in the scientific investigation of sudden unexpected death in epilepsy (SUDEP).

Anomalous Vascular Dynamics of Nanoworms within Blood Flow.

Nanomaterials have been widely used in the design of drug delivery platforms. This work computationally explores the vascular dynamics of nanoworms as drug carriers within blood flow by considering the effects of nanoworm length, stiffness, and local physiological conditions such as hematocrit. We found that nanoworms with length of 8 µm and moderate stiffness are the optimal choice as drug carriers for circulating within normal vascular network due to their lower near wall margination. Compared to those of spherical rigid particles, these nanoworms demonstrate significant demargination behaviors at hematocrit 20%, induced by the local hydrodynamic interactions. Specifically, the interactions between nanoworms and red blood cells create asymmetrical local flow fields, resulting in the demargination of nanoworms. In addition, the flexibility of nanoworms enables them to conform to the deformed shape of red blood cells under shear flow, leading to their high concentration within the core region of vessels. Therefore, the long blood circulation time of nanoworms can be partially attributed to their demargination behaviors and intertwinement with red blood cells. According to these simulation results, tuning the length and stiffness of nanoworms is the key to design drug carries with reduced near wall margination within normal vascular networks and extend their blood circulation time.

Ictal Mammalian Dive Response: A Likely Cause of Sudden Unexpected Death in Epilepsy.

Even though sudden unexpected death in epilepsy (SUDEP) takes the lives of thousands of otherwise healthy epilepsy patients every year, the physiopathology associated with this condition remains unexplained. This article explores important parallels, which exist between the clinical observations and pathological responses associated with SUDEP, and the pathological responses that can develop when a set of autonomic reflexes known as the mammalian dive response (MDR) is deployed. Mostly unknown to physicians, this evolutionarily conserved physiological response to prolonged apnea economizes oxygen for preferential use by the brain. However, the drastic cardiovascular adjustments required for its execution, which include severe bradycardia and the sequestration of a significant portion of the total blood volume inside the cardiopulmonary vasculature, can result in many of the same pathological responses associated with SUDEP. Thus, this article advances the hypothesis that prolonged apneic generalized tonic clonic seizures induce augmented forms of the MDR, which, in the most severe cases, cause SUDEP.