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Summary:pulmonary alveolar proteinosis (PAP). Abnormalities include lymphocytic infiltration around airways and vessels and the progressive accumulation of surfactant proteins, Mice deficient for the IL-3/GM-CSF/IL-5 ␤c receptor (␤cR KO) develop lung disease similar to that seen in phospholipids and macrophages within the alveolar space. [1][2][3][4][5] Previous work has defined a significant part of this disease human pulmonary alveolar proteinosis (PAP) which includes lymphocytic infiltration around airways and to be hematopoietic in origin because transplantation of wild-type (WT) bone marrow into ␤cR KO mice led to vessels and the progressive accumulation of surfactant and macrophages within the alveolar space. We investicomplete resolution of alveolar proteinosis and restoration of normal macrophage morphology. When the lungs of ␤cR gated bone marrow transplantation (BMT) as a curative treatment of PAP in ␤cR KO mice by semiquantitative KO mice were evaluated at 8 and 12 weeks after WT BMT however, it was apparent that residual lung injury was histologic analysis and evaluation of pulmonary function. BMT from wild-type (WT) donors into lethally present despite the dramatic improvement in the disease state. 6 In order to determine the precise effects of BMT in irradiated ␤cR KO recipients (WT → KO) led to the complete resolution of alveolar protein accumulation the reversal of the mutant phenotype, we examined more closely the extent of residual disease in these animals postand to normalization of BAL fluid cellularity and macrophage morphology. However, detailed microtransplant by using a semiquantitative index for histopathology, and correlated these findings to pulmonary function. scopic analysis of lung tissue revealed the persistence of significant cellular infiltrates in WT → KO recipients Our findings demonstrate that abnormal respiratory physiology and significant mononuclear cell infiltrates remain in which were equivalent to those seen in KO → KO animals. Evaluation of pulmonary function demonstrated ␤cR KO mice despite the marked improvement in alveolar protein accumulation after WT BMT. that only dynamic compliance (C dyn ) and not airway conductance (G L ) was significantly improved in the WT → KO group compared to KO → KO animals and that both of these measurements remained significantly Materials and methods abnormal when compared to WT → WT controls. We conclude, that although BMT for PAP reverses alveolar Mice and bone marrow transplantation macrophage and protein accumulation, it does not decrease the interstitial inflammatory component of this Generation of mice deficient for the ␤c receptor (␤cR KO) and methods for BMT have been described previously. 1,6 disease. The importance of this residual pathology is demonstrated by the incomplete correction of alveolar Briefly, all experimental animals were raised and housed in microisolator cages at the DNAX animal facility and have function (C dyn ) and lack of improvement in increased airway resistance (G L ). These findings may have routinely ...

In inflammatory disease states, such as hepatitis and sepsis, cholestasis is a common observation. 1,2 Although it is known that endotoxemia decreases hepatocellular bile acid uptake in vivo, the sequence of events leading to impairment of transport for bile salts is incompletely understood. The role of macrophages as mediators in endotoxemia or exposure of the liver to toxins such as alcohol or D-galactosamine, in particular through the release of proinflammatory cytokines, has been the focus of recent studies. [3][4][5] However, the question of whether macrophages are needed to mediate the cholestatic effect of inflammatory disease has not yet been clearly answered.Plasma membrane transport proteins for biliary solutes at both poles of the hepatocyte have been shown to be affected by endotoxin (lipopolysaccharide [LPS]). [6][7][8][9][10][11][12] On the canalicular membrane, mrp2, the organic anion transporter, is significantly down-regulated after LPS exposure. 8,11 In contrast, the canalicular bile acid transporter (bile salt export pump [BSEP]), is not substantively down-regulated during endotoxemia. 11 Several investigators have focused attention on the response of the sodium-taurocholate-cotransporting polypeptide (ntcp), the dominant transport protein for bile salts on the basolateral plasma membrane in a variety of inflammatory models. The effects of LPS or proinflammatory cytokines on ntcp have been the subject of intense investigation using in vivo models, 9,10,12 perfused rat liver, 6 hepatocyte cell culture, 13,14 and membrane preparations from the rat liver. 9,10 These studies show that ntcp protein expression and messenger RNA (mRNA) levels are down-regulated in the presence of LPS or proinflammatory cytokines. Recent studies provide evidence for hepatocellular alterations in regulatory nuclear transcription factors acting on the ntcp promoter 12 during endotoxemia. However, less information has been gained regarding extracellular mediators of endotoxin-induced cholestasis. It has been postulated but not proven that macrophages are responsible for the processing of LPS and the release of cytokines, which, in turn, adversely affect bile acid transport on the basolateral domain of the hepatocyte. 2 In this study, we show that LPS has a cholestatic effect on a hepatoma cell line only if macrophages are used as mediators. Tumor necrosis factor ␣ (TNF-␣), interleukin 1␤ (IL-1␤), and IL-6 were identified as effector cytokines causing diminished bile acid transport across the basolateral membrane and decreased expression of ntcp mRNA. Macrophage release of

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