The multifunctional cytokine interleukin (IL)-6 has been shown to modulate inflammation and angiogenesis. In a mouse model of lung angiogenesis induced by chronic left pulmonary artery ligation (LPAL), we previously showed increased expression of IL-6 mRNA in lung homogenates 4 h after the onset of pulmonary ischemia. To determine whether IL-6 influences both new vessel growth and inflammatory cell influx, we studied wild-type (WT) and IL-6-deficient C57Bl/6J (KO) mice after LPAL (4 h and 1, 7, 14 days). We measured IL-6 protein of the lung by ELISA, the lavage cell profile of the left lung, and new systemic vessel growth with radiolabeled microspheres (14 days after LPAL) in WT and KO mice. We confirmed a 2.4-fold increase in IL-6 protein in the left lung of WT mice compared with right lung 4 h after LPAL. A significant increase in lavaged neutrophils (7.5% of total cells) was observed only in WT mice 4 h after LPAL. New vessel growth was significantly attenuated in KO relative to WT (0.7 vs. 1.9% cardiac output). In an additional series, treatment of WT mice with anti-neutrophil antibody demonstrated a reduction in lavaged neutrophils 4 h after LPAL; however, IL-6 protein remained elevated and neovascularization to the left lung (2.3% cardiac output) was not altered. These results demonstrate that IL-6 plays an important modulatory role in lung angiogenesis, but the changes are not dependent on trapped neutrophils.

We previously showed increased expression of the ELR+, CXC chemokines in the lung after left pulmonary artery obstruction. These chemokines have been shown in other systems to bind their G protein-coupled receptor, CXCR(2), and promote systemic endothelial cell proliferation, migration, and capillary tube formation. In the present study, we blocked CXCR(2) in vivo using a neutralizing antibody and also studied mice that were homozygous null for CXCR(2). To estimate the extent of neovascularization in this model, we measured systemic blood flow to the left lung 14 days after left pulmonary artery ligation (LPAL). We found blood flow significantly reduced (67% decrease) with neutralizing antibody treatment compared with controls. However, blood flow was not altered in the CXCR(2)-deficient mice compared with wild-type controls after LPAL. To test for ligand availability, we measured macrophage inflammatory protein (MIP)-2 in lung homogenates after LPAL, because this is the predominant CXC chemokine previously shown to be increased after LPAL (22). MIP-2 protein was two- to fourfold higher in the left lung relative to the right lung in all treatment groups 4 h after LPAL and this increase did not differ among groups. We speculate that the CXCR(2)-deficient mice have compensatory mechanisms that mitigate their lack of gene expression and conclude that CXCR(2) contributes to chemokine-induced systemic angiogenesis after pulmonary artery obstruction.

Maternal iron deficiency anemia (IDA) is associated with risk of adverse perinatal outcomes. Oral iron is recommended to reverse anemia, but has gastrointestinal toxicity and frequent non-adherence. Intravenous (IV) iron is reserved for intolerance of, or unresponsiveness to, oral therapy, malabsorption, and severe anemia (1% with hemoglobin [Hgb] levels <7 g/dL). With rare (<100 per one million) adverse events (AEs) ability to infuse a sufficient dose of low molecular weight iron dextran (LMWID) over 60 min, LMWID is an attractive option. This study demonstrated safety and efficacy of rapid IV infusion of 1,000 mg LMWID to gravidas with moderate to severe IDA. An observational treatment study of 1,000 mg LMWID administered over 1 hr for IDA in 189 consecutive, unselected second and third trimester gravidas after oral iron failure was conducted. All received a test dose of 25 mg LMWID and were monitored for AEs during the 60-min infusion. No premedication was administered unless more than one drug allergy or asthma was present in which case IV methylprednisolone was administered. All were followed through pregnancy and delivery. Monitored parameters included Hgb, mean corpuscular volume, serum ferritin, and percent transferrin saturation. About 189 subjects received 1,000 mg LMWID. No serious AEs occurred. About 2% experienced transient infusion reactions. Hgb improved by 1-1.9 g/dL in 82% and 2 g/dL in 24%. Second trimester treatment was not associated with greater Hgb improvement than third trimester treatment. Anemia resolved in 95%. Administration of a single large dose of IV LMWID was effective, safe, and convenient.

A role for inflammation in modulating the extent of angiogenesis has been shown for a number of organs. The present study was undertaken to evaluate the importance of leukocyte subpopulations for systemic angiogenesis of the lung after left pulmonary artery ligation (LPAL) in a mouse model of chronic pulmonary thromboembolism. Since we (24) previously showed that depletion of neutrophils did not alter the angiogenic outcome, we focused on the effects of dexamethasone pretreatment (general anti-inflammatory) and gadolinium chloride treatment (macrophage inactivator) and studied Rag-1(-/-) mice (T/B lymphocyte deficient). We measured inflammatory cells in bronchoalveolar lavage fluid and lung homogenate macrophage inflammatory protein-2 (MIP-2) and IL-6 protein levels within 24 h after LPAL and systemic blood flow to the lung 14 days after LPAL with labeled microspheres as a measure of angiogenesis. Blood flow to the left lung was significantly reduced after dexamethasone treatment compared with untreated control LPAL mice (66% decrease; P < 0.05) and significantly increased in T/B lymphocyte-deficient mice (88% increase; P < 0.05). Adoptive transfer of splenocytes (T/B lymphocytes) significantly reversed the degree of angiogenesis observed in the Rag-1(-/-) mice back to the level of control LPAL. Average number of lavaged macrophages for each group significantly correlated with average blood flow in the study groups (r(2) = 0.9181; P = 0.01 different from 0). Despite differences in angiogenesis, left lung homogenate MIP-2 and IL-6 did not differ among study groups. We conclude that inflammatory cells modulate the degree of angiogenesis in this lung model where lymphocytes appear to limit the degree of neovascularization, whereas monocytes/macrophages likely promote angiogenesis.