Macrophages are ubiquitous in the stromal compartment of tissues under normal physiological conditions and the number of these cells increases markedly with the onset and progression of many pathological states. The mechanisms underlying this response are well described in such conditions as wound healing and malignant tumors, where tissue-specific signals enhance the extravasation of blood monocytes and their subsequent differentiation into macrophages. Recent evidence suggests that macrophages may also be stimulated by microenvironmental factors present in diseased tissues to perform distinct, tissue-specific activities. One such factor, hypoxia (low oxygen tension), results from insufficient vascular perfusion of a given tissue. Various studies have shown that experimental hypoxia alters the morphology, expression of cell surface markers, viability, phagocytosis, metabolic activity, and release of cytokines by macrophages. Here we review the evidence for these macrophage responses to hypoxia, the involvement of co-stimuli, and their implications for the role of macrophages in various disease processes. Because the intracellular mechanisms mediating the effects of hypoxia on gene expression in other cell types have been characterized recently, we discuss their possible involvement in the effects of hypoxia on gene expression in macrophages.

Angiogenesis is essential to the growth and metastasis of solid tumours. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic cytokine that is overexpressed in malignant tumours such as invasive carcinoma of the breast. The low oxygen tensions (hypoxia) present in these tumours are known to up-regulate the expression of VEGF by tumour cells. Human macrophages also respond to hypoxia by increasing their release of VEGF in vitro, although the effect of hypoxia on VEGF expression by macrophages in vivo has yet to be demonstrated. The present study compared the expression of VEGF by macrophages in areas of low and high vascularity in 24 invasive breast carcinomas (12 lobular, 12 ductal). The cellular distributions of VEGF protein, CD31 (vessels), and CD68 (macrophages) were compared in sequential sections for each tumour. In ten tumours, both tumour cells and macrophages were immunoreactive for VEGF protein. Use of non-isotopic in situ hybridization to localize VEGF mRNA showed that these cell types also expressed VEGF mRNA. No significant differences in the cellular distribution of VEGF protein were found between lobular and ductal carcinomas. In all tumours, macrophages accumulated in higher numbers in poorly vascularized than in highly vascularized areas. In VEGF-positive tumours, macrophages were immunoreactive for VEGF only in avascular areas where tumour cells also expressed VEGF. This suggests that VEGF expression by these two cell types may be regulated by the same microenvironmental stimuli in breast carcinomas. In addition, significantly more macrophages were present in poorly vascularized areas of VEGF-positive than VEGF-negative tumours. This suggests that VEGF may exert a chemotactic action on macrophages in vivo and guide their migration into avascular tumour sites.

Purpose Use of administrative or population-based databases for post-marketing pharmacoepidemiology research in patients with end-stage liver disease (ESLD) has been limited by the difficulty of accurately identifying such patients. Algorithms to identify patients with ESLD using ICD-9-CM codes have not been developed outside of the Veterans Affairs healthcare setting. Methods We queried electronic medical records at two tertiary care hospitals to identify patients with ICD-9-CM codes indicative of ESLD. Coding algorithms were developed to identify patients with confirmed ESLD, and these were tested to determine their positive predictive value (PPV). Results The presence of one inpatient or outpatient ICD-9-CM code for: a) cirrhosis, b) chronic liver disease, and c) a hepatic decompensation event yielded a PPV of 85.2% (167/196; 95% CI: 79.4%–89.9%). The PPV increased to 89.3% (150/168; 95% CI: 83.6%–93.5%) when the algorithm required 2 or more ICD-9-CM codes for a hepatic decompensation. However, an algorithm requiring only one ICD-9-CM code for a) cirrhosis and b) a hepatic decompensation event, in the absence of a chronic liver disease code, yielded a PPV of 85.7% (30/35; 95% CI: 69.7%–95.2%). Conclusions A coding algorithm that includes at least one ICD-9-CM code for cirrhosis plus one ICD-9-CM code for a hepatic decompensation event has a high PPV for identifying patients with ESLD. The inclusion of at least 2 codes indicative of chronic liver disease increased the PPV. This algorithm can be used in future epidemiologic studies to examine the outcomes of a variety of long-term medical therapies in patients with ESLD.

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