Medium osmolarity sensitively regulates Kupffer cell func-are not fully understood, activation of Kupffer cells has been tions like phagocytosis and prostaglandin (PG) and cytokine identified as an important mechanism promoting further production. Betaine and taurine, recently identified as osmoliver injury during early reoxygenation in several experimenlytes in liver cells, interfere with these effects. Because Kupffer tal models following warm 4-6 and cold ischemia. 7,8 Kupffer cell activation is an important pathogenic mechanism in ischcell activation results in increased formation of reactive oxyemia-reoxygenation injury, the influence of osmolarity and gen species, release of cytokines such as interleukin-1, tumor osmolytes was investigated in a rat liver perfusion model of necrosis factor a (TNF-a), and platelet activating factor, as warm ischemia. Livers were perfused with different medium well as eicosanoids like prostaglandins (PG) and thromboxosmolarities for 60 to 90 minutes in the absence of oxygen, ane. 4,5,[7][8][9][10] These mediators act on other cells in the liver, e.g., followed by another 90 minutes of reoxygenation. Lactate PGs and thromboxane disturb microcirculation by vasocondehydrogenase (LDH) leakage into the effluent perfusate durstriction; reactive oxygen species may inactivate antiproteing the hypoxic and the reoxygenation period was eight-to ases; and cytokines induce the expression of adhesion mole-10-fold higher with a medium osmolarity of 385 mosmol/L cules promoting the infiltration of neutrophils. [11][12][13] Recently, than in normo-osmolarity, and further decreased with hypoactivation of mitogen-activated protein kinases during reoxyosmolar perfusion buffer. Betaine and taurine addition to the genation following cold ischemia was demonstrated in transperfusate in near physiological concentrations decreased hypplanted rat livers that may be perpetuated by TNF-a. 14 The oxia-reoxygenation-induced LDH leakage, aspartate transimportance of Kupffer cells is further substantiated by the aminase (AST) leakage, and perfusion pressure increase in protective effect of Kupffer cell inactivation by gadolinium hyperosmolar and normo-osmolar perfusions. Stimulation of chloride or methyl palmitate treatment in ischemia-reperfu-PGD 2 , PGE 2 , thromboxane B 2 (TXB 2 ), and tumor necrosis sion injury, 5,15 although a recent study questioned these refactor a (TNF-a) release, as well as induction of carbon upsults. 16 take by the liver during reoxygenation, were suppressed by
In rat livers, Kupffer cell function is regulated by changes betaine and taurine, pointing to an interference of these osmoof ambient osmolarity: endotoxin-induced PGE 2 , PGD 2 , and lytes with Kupffer cell function. In contrast, endothelial cell thromboxane B 2 (TXB 2 ) formation and cyclooxygenase-2function as assessed by hyaluronic acid (HA) uptake was not expression are stimulated seven-to 10-fold when ambient influenced. It is concluded that warm ischemia-reoxygenation osmolarity increases from 300 to 350 mosmol/L. 17 TNF-a injury in rat liver is aggravated by hyperosmolarity and attenuproduction and phagocytosis by Kupffer cells are also sensiated by hypo-osmolarity. The osmolytes betaine and taurine tive to osmolarity changes. 18,19 Recently, betaine and taurine have a protective effect, presumably by inhibition of Kupffer were identified as osmolytes in macrophages including Kupfcell activation. (HEPATOLOGY 1997;26:1560-1566.) fer cells. [20][21][22] Organic osmolytes are compounds that are accumulated or released by the cells in response to hyperosmotic Ischemic liver injury is of major clinical relevance during cell shrinkage or hypo-osmotic cell swelling, respectively, organ transplantation and in shock syndromes. Loss of cell to maintain cell volume homeostasis. Osmolytes must be function and cell injury during the ischemic period are nonperturbing solutes that do not interfere with protein thought to be caused by adenosine triphosphate depletion, function even at high intracellular concentrations. [23][24][25] Thereactivation of nonlysosomal proteases, and glucose deplefore, only a few classes of organic compounds, i.e., polyols tion. 1-3 Although the exact pathophysiological mechanisms (inositol, sorbitol), methylamines (betaine, a-glycero-phosphocholine), and certain amino acids such as taurine, have evolved as osmolytes in living cells. In mammals, osmolytes have been identified in astrocytes, renal medullary cells, and
Abbreviations: TNF-a, tumor necrosis factor a; PG, prostaglandin; TXB2, thromlens epithelia. [26][27][28] Hyperosmotic exposure induces betaine boxane B2; LDH, lactate dehydrogenase; AST, aspartate transaminase; HA, hyaluronic acid.
transporter BGT1 and taurine transporter messenger RNA