Chronic rejection after lung transplantation, manifesting as bronchiolitis obliterans syndrome (BOS), has become the dominant challenge to long-term patient and graft survival. In order to elucidate risk factors for development of BOS we utilized the 1995 revision of the working formulation for the classification of lung allograft rejection (), and devised a quantitative method to retrospectively study lung transplant biopsies from all patients who survived at least 90 d. All transbronchial biopsies were regraded 0 to 4 for acute perivascular rejection and lymphocytic bronchitis/bronchiolitis (LBB), and the grades were totaled over a period of time to give two scores, respectively, for each patient. Also examined were timing of acute rejection and LBB episodes and decreased immunosuppression defined as two or more cyclosporine A levels < 200 ng/ml. Sixty-six patients with BOS and 68 with no BOS (NBOS) satisfied our criteria for inclusion in the study. Demographics including age, sex, and primary diagnoses were similar. The mean perivascular score for BOS was 6.2 over a mean follow-up of 822 d (range, 113 to 2,146) compared with 3.2 for NBOS over 550 d (range, 97 to 1,734) mean follow-up. Airway scores were 5.3 and 1.7, respectively, for the same follow-up periods. There was no correlation between length of follow-up and rejection or LBB scores, although mean length of follow-up for the two groups was significantly different. Late acute rejection and LBB were significantly associated with BOS as was decreased immunosuppression. In addition to perivascular rejection, LBB, late acute rejection, and decreased immunosuppression are significant risk factors for the development of BOS. Analysis of the current data leads us to believe that LBB, in the absence of infection, is in fact a manifestation of acute rejection, with similar implications for graft function as acute perivascular rejection.

Increased gut permeability (leaky gut) and endotoxin-mediated Kupffer cell activation are proposed as the mechanisms of alcoholic liver injury. Although ethanol feeding is shown to sensitize the liver for injury induced by parental administration of lipopolysaccharide (LPS), how enteral LPS loading affects alcoholic liver injury is yet to be tested. The present study provides direct evidence for enhanced entrance to portal circulation of LPS enterally administered to the intragastric ethanol infusion model. Portal and systemic blood endotoxin levels increased to 43.0 ؎ 4.1 and 6.2 ؎ 4.3 pg/mL at 2 hours following enteral LPS administration (5 mg/kg) in alcohol-fed animals, while no such increases were observed in pair-fed controls. However, endotoxin levels in systemic blood of alcohol-fed rats were reduced to 0 to 1.5 pg/mL 16 hours after LPS administration. Development of effective therapies for alcoholic liver disease (ALD) depends on the understanding of the mechanisms that contribute to the disease process. Experimental and clinical findings to date suggest that endotoxin and proinflammatory cytokines constitute the main effector molecules in alcohol-induced liver injury. 1-5 Endotoxin (lipopolysaccharide [LPS]), a prominent agonist of Kupffer cells, interacts with its specific carrier, LPS-binding protein (LBP) to stimulate hepatic macrophages via binding of the LPS-LBP complex to the CD14 receptor. [6][7][8] This stimulation results in the release of proinflammatory mediators by the macrophages and consequent immunological and cytotoxic events leading to development of liver injury.In rats given continuous infusion of ethanol and a high-fat diet, focal hepatic inflammation and necrosis may be evident after 4 weeks 9 and are accompanied by the pretranslational induction of proinflammatory cytokine expression in Kupffer cells. 10 Hepatic expression of tumor necrosis factor ␣ (TNF-␣) mRNA is induced when pathological changes in the liver become evident. 11 Simultaneous increases in the plasma endotoxin level and mRNA expression of proinflammatory cytokines are noted in ethanol-fed rats. 12,13 Taken together, these results suggest that induction of progressive alcoholic liver injury may require increased plasma endotoxin levels as a mechanism of proinflammatory cytokine induction. In support of this notion, alcoholic patients with chronic liver disease exhibit increased intestinal permeability. 14,15 Patients with alcoholic cirrhosis have higher endotoxin levels than heavy drinkers without cirrhosis and healthy controls. 16 Peripheral blood mononuclear cells isolated from patients with alcoholic cirrhosis secrete more interleukin-6, interleukin-8, and TNF-␣ than those from healthy controls. 17,18 In the intragastric infusion model, plasma endotoxin levels and enhanced LBP and CD14 expression are correlated with the presence of liver necrosis, [19][20][21][22] and the treatment of the animals with lactobacillus 23 or antibiotics 24 ameliorates alcoholic liver injury. Furthermore, intestinal permeability is als...

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Intermethod variability in 25(OH)D assays continues to limit our progress toward the establishment of reference values for 25(OH)D in health and our efforts to gain a better understanding of the role of vitamin D insufficiency as a risk factor for disease.

Because only the alcoholics with chronic liver disease had increased intestinal permeability, we conclude that a "leaky" gut may be a necessary cofactor for the development of chronic liver injury in heavy drinkers.

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