The microcirculation as a functional system

Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Critical care (London, England) (Impact Factor: 4.48). 02/2005; 9 Suppl 4(Suppl 4):S3-8. DOI: 10.1186/cc3751
Source: PubMed


This review examines experimental evidence that the microvascular dysfunction that occurs early in sepsis is the critical first stage in tissue hypoxia and organ failure. A functional microvasculature maintains tissue oxygenation despite limitations on oxygen delivery from blood to tissue imposed by diffusion; the density of perfused (functional) capillaries is high enough to ensure appropriate diffusion distances, and arterioles regulate the distribution of oxygen within the organ precisely to where it is needed. Key components of this regulatory system are the endothelium, which communicates and integrates signals along the microvascular network, and the erythrocytes, which directly monitor and regulate oxygen delivery. During hypovolemic shock, a functional microvasculature responds to diminish the impact of a decrease in oxygen supply on tissue perfusion. However, within hours of the onset of sepsis, a dysfunctional microcirculation is, due to a loss of functional capillary density and impaired regulation of oxygen delivery, unable to maintain capillary oxygen saturation levels and prevent the rapid onset of tissue hypoxia despite adequate oxygen supply to the organ. The mechanism(s) responsible for this dysfunctional microvasculature must be understood in order to develop appropriate management strategies for sepsis.

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    • "One of the proposed mechanisms for the deficient oxygen delivery in sepsis is the occlusion of capillaries [34]. Accumulating evidences to date support that leukocyte is a likely candidate to occlude capillaries [35]. Therefore, we examined the LA level in the lung tissues and found that a significant increase of LA was observed in lung tissues from LPS-stimulated mice but not from LPS-stimulated mice with Gu-4 treatment. "
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    ABSTRACT: Systemic leukocyte activation and disseminated leukocyte adhesion will impair the microcirculation and cause severe decrements in tissue perfusion and organ function in the process of severe sepsis. Gu-4, a lactosyl derivative, could selectively target CD11b to exert therapeutic effect in a rat model of severe burn shock. Here, we addressed whether Gu-4 could render protective effects on septic animals. On a murine model of endotoxemia induced by lipopolysaccharide (LPS), we found that the median effective dose (ED50) of Gu-4 was 0.929 mg/kg. In vivo treatment of Gu-4 after LPS challenge prominently attenuated LPS-induced lung injury and decreased lactic acid level in lung tissue. Using the ED50 of Gu-4, we also demonstrated that Gu-4 treatment significantly improved the survival rate of animals underwent sepsis induced by cecal ligation and puncture. By adhesion and transwell migration assays, we found that Gu-4 treatment inhibited the adhesion and transendothelial migration of LPS-stimulated THP-1 cells. By flow cytometry and microscopy, we demonstrated that Gu-4 treatment inhibited the exposure of active I-domain and the cluster formation of CD11b on the LPS-stimulated polymorphonuclear leukocytes. Western blot analyses further revealed that Gu-4 treatment markedly inhibited the activation of spleen tyrosine kinase in LPS-stimulated THP-1 cells. Gu-4 improves the survival of mice underwent endotoxemia and sepsis, our in vitro investigations indicate that the possible underlying mechanism might involve the modulations of the affinity and avidity of CD11b on the leukocyte. Our findings shed light on the potential use of Gu-4, an interacting compound to CD11b, in the treatment of sepsis and septic shock.
    PLoS ONE 02/2012; 7(2):e30110. DOI:10.1371/journal.pone.0030110 · 3.23 Impact Factor
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    • "The microcirculation plays a crucial role in local distribution of oxygen and other nutrients to meet cellular metabolic demand [37]. Microcirculatory dysfunction in early sepsis is considered to play a prominent pathophysiologic role [38] [39]. "
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    ABSTRACT: This long-term septic model exhibited an early decline in tissue oxygenation, the degree of which related to predicted mortality. Clinical and biochemical deterioration, however, progressed despite cardiovascular recovery. Early circulatory dysfunction may thus be an important trigger for downstream processes that result in multi-organ failure. Furthermore, the utility of tissue PO2 monitoring to highlight the local oxygen supply-demand balance, and dynamic O2 challenge testing to assess microcirculatory function merit further investigation.
    Intensive Care Medicine 04/2011; 37(7):1192-200. DOI:10.1007/s00134-011-2227-z · 7.21 Impact Factor
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    • "involving the microcirculation affects tissue haemodynamics and oxygenation [1] [2] [5]; and understanding of the physiologic mechanisms that determine how a functional microcirculation provides for and responds to changes in oxygen demand [11] [12] [13]. Prior urologic research has identified that functional and structural abnormalities in the bladder are associated with decreased blood flow in the organ's microcirculation. "

    International Journal of Spectroscopy 01/2011; 2011. doi:10.1155/2011/814179.(1687-9449). DOI:10.1155/2011/814179
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