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* COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; and
Department of Medicine and
Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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B activation (4), proinflammatory mediator release (5, 6), expression of matrix metalloproteinases (7, 8, 9), and by increasing expression of constitutive NO synthase (10), peroxisome proliferator-activated receptor (PPAR)3
(11), PPAR
(4), and TGF
1 (12). Statins also suppress the adaptive immune response by inhibiting IFN--inducible MHC class II expression (13), decreasing expression of CD40/CD40L (14), and by direct blockade of LFA-1 (15). These pleiotropic, anti-inflammatory effects have important therapeutic implications, because 1) statins effectively treat animal models of sepsis, rheumatoid arthritis, acute lung injury, asthma, and emphysema (2, 16, 17, 18, 19), and 2) clinically, statins have a promising therapeutic role in the acute coronary syndrome, stabilization of carotid artery plaques, sepsis syndrome, lung allograft rejection, and rheumatoid arthritis (7, 20, 21, 22, 23, 24). Therefore, statins appear to be emerging as a new class of immunomodulators, surpassing their originally envisaged role as cholesterol lowering drugs. The immunomodulatory effects of statins are largely cholesterol independent; instead, they appear to depend upon the ability of statins to posttranslationally modify an extensive array of intracellular signaling molecules, including the Rho family of GTPases (1). Rho GTPases (e.g., RhoA, Rac-1, and Cdc42) are molecular switches, which for function, depend upon the covalent attachment of lipid adducts (prenylation) that direct membrane insertion, localization, and protein:protein interaction (25, 26). Statins regulate prenylation of Rho-GTPases by blocking 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which decreases production of mevalonate, and downstream prenylation substrates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) (see Fig. 1). These statin properties suggest a cholesterol-independent mechanism through which they may have far-reaching, regulatory effects.
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Indeed, our data demonstrate that statins are potent inducers of efferocytosis in vitro and in vivo in an HMG CoA-reductase dependent manner. Statins appear to exert their effect, not by suppressing cholesterol, but by disproportionately suppressing the prenylation and membrane localization of RhoA. Finally, these data may have therapeutic implications for the treatment of chronic inflammatory diseases of the lung, because statins augment efferocytosis in the naive murine lung and in alveolar macrophages obtained from patients with COPD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The study was approved by, and performed in accordance with, the ethical standards of the institutional review board on human experimentation at National Jewish Medical and Research Center. Written informed consent was obtained from each subject.
Experimental animals
Mice were housed and studied under institutional animal care and use committee-approved protocols in the animal facility of National Jewish Medical and Research Center. Experiments were performed on 8- to 12-wk-old, age-matched, female ICR mice (Harlan Sprague Dawley).
Primary cell isolation and culture
Human monocyte-derived macrophages (HMDMs) and neutrophils were isolated and prepared from normal blood, as previously described (44). HMDMs were cultured in X-vivo medium (Cambrex BioScience) with 10% pooled human serum at 37°C in 10% CO2 for 7 days before use.
Human alveolar macrophages were isolated by bronchoalveolar lavage from patients with Global Initiative for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 COPD as described (31, 45). The right middle lobe was lavaged with 100 ml of 0.9% saline solution at room temperature. Human alveolar macrophages were resuspended in X-vivo medium (Cambrex BioScience) and were plated on baked glass coverslips in 24-well tissue-culture plates (BD Biosciences) at 5.0 x 105 alveolar macrophages/well.
Murine thymocytes were isolated from the thymi of 3- to 4-wk-old, female ICR mice, by passing thymi through a 40-µm strainer (Fisher Scientific) to separate individual cells.
Cell lines and culture
The human Jurkat leukemia T cell line was obtained from the American Type Culture Collection and cultured in RPMI 1640 with 10% FBS, supplemented with penicillin-streptomycin-glutamine, and incubated at 37°C in 10% CO2 (31, 46).
Induction of apoptosis
Apoptosis was induced in human neutrophils, Jurkat T cells, and murine thymocytes by exposure to UV irradiation at 312 nm (Fotodyne) for 10 min, as previously described (31). Human neutrophils were cultured in RPMI 1640 with 0.5%, low-endotoxin BSA (Sigma-Aldrich) at 37°C in 10% CO2 for 2.5 h before use. Jurkat T cells were cultured in RPMI 1640 with 10% FCS at 37°C in 5% CO2 for 3.5 h before use. Neutrophils and Jurkat T cells treated in this way were 
80% apoptotic by nuclear condensation. Thymocytes were cultured in RPMI 1640 with 10% FCS at 2 x 106 cells/ml at 37°C in 5% CO2 for 3 h. In Fig. 5E, thymocytes were cultured in RPMI 1640 with 0.5% low-endotoxin BSA at 4 x 106 cells/ml overnight without exposure to UV irradiation. Thymocytes exposed to UV irradiation were 90% annexin V positive and 30% propidium iodide positive. Thymocytes cultured overnight were 80% annexin V positive and 60% propidium iodide positive.
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Lovastatin (Sigma-Aldrich) was converted to its active form by dissolving 25 mg of the lactone form in 500 µl of 100% ethanol, heated to 50°C, alkalinized by adding 250 µl of 0.6 M NaOH, and incubated at 50°C for 2 h. After incubation, the solution was neutralized with 0.4 M HCl at pH 7.5. Aliquots of stock solution were stored frozen at –20°C until used (47, 48).
In vitro phagocytosis assays
Phagocytic assays were performed on day 7 HMDMs, as previously described (31). Briefly, apoptotic human neutrophils were added to HMDMs at a 5:1 ratio (apoptotic cell to HMDM) and incubated at 37°C in 10% CO2 for 40 min in 500 µl of X-Vivo medium. HMDMs were washed gently with cold PBS to remove uningested cells, fixed, and stained with a modified Wright-Giemsa (Fisher Scientific). Phagocytosis was determined by visual inspection of samples and was expressed as the phagocytic index (PI), as described (49). Each condition was tested in duplicate and a minimum of 400 HMDMs were counted per condition. In all cases, during analysis, the reader was blinded to the sample identification.
HMDMs were pretreated with 0–10 µM lovastatin for 4–120 h before experimentation. Phagocytosis assays were then performed in the presence and absence of the following reagents at the indicated concentrations and for the indicated times: mevalonate (Sigma-Aldrich), GGPP (Sigma-Aldrich), and FPP (Sigma-Aldrich). Inhibitors of farnesyltransferase (FTI-276; Calbiochem-Novabiochem) and geranylgeranyltransferase I (GGTI-2133; Calbiochem-Novabiochem) were added to HMDMs 8 h before experimentation. FTI-276 inhibits farnesyltransferase with an IC50 = 0.5 nM, and geranylgeranyltransferase I at a much higher IC50 = 50 nM. GGTI-2133 inhibits geranylgeranyltransferase I with an IC50 = 38 nM, and farnesyltransferase at a much higher IC50 = 5.4 µM.
In vivo phagocytosis assays
To test the effect of lovastatin and mevalonate on uptake of apoptotic cells, mice were divided into four groups and treated as follows: 1) control group, treated with vehicle (0.5% carboxymethylcellulose sodium, 0.9% sodium chloride, 0.4% polysorbate 80, 0.9% benzyl alcohol in deionized water) by gavage and PBS by i.p. injection; 2) lovastatin group, treated with activated lovastatin (10 mg/kg) in vehicle by gavage and PBS by i.p. injection; 3) mevalonate group, treated with vehicle by gavage and 10 mg/kg l-mevalonate by i.p. injection; 4) lovastatin/mevalonate group, treated with of lovastatin (10 mg/kg) in vehicle by gavage and mevalonate (10 mg/kg) by i.p. injection. Mice were treated three times, spaced within 30 h, before the time of experimentation.
Apoptotic thymocytes were instilled intratracheally as previously described (45). Briefly, mice were anesthetized with Avertin, following which 10 x 106 Cell Tracker Red-stained (Molecular Probes) apoptotic thymocytes, suspended in 50 µl of PBS, were instilled intratracheally using a modified animal feeding needle (Fisher Scientific). Forty minutes later, whole lung bronchoalveolar lavage was performed with a total of 5 ml of ice-cold PBS. Lavage cells were fixed and stained with modified Wright’s Giemsa (Fisher Scientific). Phagocytosis was determined by visual inspection of samples (see Fig. 5A), as previously described (45, 50), and was expressed a PI. A minimum of 400 alveolar macrophages were counted blindly.
Recovered apoptotic thymocytes were determined as follows. Total lavage cells (including erythrocytes) were counted using a hemacytometer. The percentage of free thymocytes in the lavage was determined by FACS analysis (Fig. 5B). Macrophages were excluded, based upon macrophage forward-side scatter characteristics, F4/80 staining, and autofluorescence. Total recovered thymocytes were calculated by multiplying total lavage cells by the percentage of Cell Tracker Red-positive cells.
FACS analysis
FACS analysis was done as previously described (31). Briefly, HMDMs were suspended in HBSS containing 2% FCS (Gemini Bio-Products), blocked with human serum, except cells for FcR staining, incubated with 5 µg of the primary Ab for 30 min on ice, washed twice, then incubated with the secondary Ab (1/50 dilution) on ice for 30 min. Washed macrophages were analyzed on a FACScan cytometer using CellQuest Pro (BD Biosciences) and FloJo (Tree Star) software.
Abs used in FACS analysis were as follows: BD Biosciences/BD Pharmingen Abs include mouse monoclonal anti-human CD36 IgM, anti-human CD44 IgG1, anti-human integrin 3 IgG1, anti-human CD32 (FcRIIa) IgG2b, and mouse monoclonal IgG1, IgG2a, IgG2b, IgM, isotype controls (Chemicon International) Abs include mouse monoclonal anti-human integrin V5 IgG1 (Affinity BioReagent) Abs include chicken polyclonal anti-human calreticulin IgY (American Diagnostica) Abs include mouse monoclonal anti-human -chain CD91 IgG1. Mouse monoclonal anti-human PS recognition structure IgM (217) was prepared in this laboratory as previously described (27). Jackson ImmunoResearch Laboratories Abs include chicken IgY isotype control, Cy-3 goat IgG anti-mouse IgM, and Cy-3 goat IgG anti-mouse IgG, and Cy-3 goat anti-chicken IgY.
Western blotting
HMDM membrane fractions were prepared and separated on SDS-PAGE as described previously (51, 52). Briefly, HMDMs plated on 10-cm tissue-culture dish were harvested and resuspended in PBS. Pelleted cells were lysed by Reporter Lysis Buffer (Promega) and by repeated freeze-thaw cycles. Cell lysates were spun down at 3,000 rpm for 10 m. Supernatants were collected and spun-down at 10,000 x g for 45 m. The pellet was solubilized in lysate buffer (20 mM HEPES (pH 7.4), 150 mM NaCl, 1 mM DTT, 1% Triton X-100). Samples were run on a 7.5% SDS-PAGE gel, transferred to nitrocellulose, blocked with 3% milk, and sequentially incubated with primary and secondary Abs. Total protein was measured by the BCA Protein Assay kit (Pierce) and equivalent amounts were loaded into gels. Immunoblotting was performed using mAbs against RhoA, RhoB, and RhoC (clone 55, 3 µg/ml; Upstate Biotechnology) and Rac-1 (clone 23A8, 1 µg/ml; Upstate Biotechnology), and immunodetection was accomplished using a mouse anti-mouse HRP-conjugated secondary Ab (1/10,000). Membranes were developed using Amersham ECL system (Amersham Biosciences).
Statistics
The means were analyzed using ANOVA for multiple comparisons; when ANOVA indicated significance, the Dunnett’s method was used to compare groups with an internal control. For all other experiments in which two conditions were being compared, a Student’s t test assuming equal variance was used. All data were analyzed using JMP (version 3) Statistical Software for Macintosh (SAS Institute) and are presented ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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We tested the effect of statins on efferocytosis by incubating HMDMs with lovastatin for 6–48 h. Lovastatin (5 µM) increased efferocytosis as early as 6 h (Fig. 1B). However, at 24 h, lovastatin increased efferocytosis in a dose-dependent fashion, exerting a maximum effect at 10 µM. In contrast, lovastatin had no effect on binding of apoptotic cells to HMDMs (Fig. 1C). Lovastatin (1 µM) also increased efferocytosis in HMDMs after 5 days of treatment compared with untreated cells, suggesting that the effect was prolonged (Fig. 1D).
The effect of lovastatin on efferocytosis is dependent on HMG-CoA reductase
Most, but not all, statin effects are related to their ability to competitively block HMG-CoA reductase, and thereby decrease production of multiple intermediates in the cholesterol biosynthetic pathway. Mevalonate is the initial product of HMG-CoA reductase (Fig. 1A) and mevalonate levels are decreased by statin therapy. We performed "rescue" experiments with mevalonate to determine whether lovastatin was acting through an HMG-CoA reductase-dependent pathway (Fig. 1E). Mevalonate reversed the ability of lovastatin to potentiate efferocytosis, confirming HMG-CoA reductase dependency. In contrast, lovastatin suppressed phagocytosis of IgG-opsonized erythrocytes through the FcR, as has recently been shown (53, 54), and this also appeared to be dependent on HMG-CoA reductase (Fig. 1F).
Lovastatin does not affect expression of efferocytosis receptors
We considered that lovastatin may exert its positive effect on efferocytosis by increasing expression of key uptake receptors, especially because statins were recently reported to increase the expression of CD36, a well-known efferocytosis receptor (55). Contrary to this report, we found that lovastatin had no effect on expression of HMDM efferocytosis receptors (i.e., V5, 3, CD91, calreticulin, CD36, CD44, CD14) or the FcRIIa (Fig. 2). Lovastatin also had no effect on staining by mAb 217. The protein target of mAb 217 was originally thought to be the phosphatidylserine receptor, but is now not known.
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Statins regulate the posttranslational modification of hundreds of proteins by controlling the production of key substrates of protein prenylation, such as FPP and GGPP. Because mevalonate is an upstream precursor of both FPP and GGPP, statins ultimately decrease their levels as well. We performed dose-response rescue experiments with GGPP and FPP, and found that both reversed lovastatin-enhanced efferocytosis, albeit with different potencies (Fig. 3, A and B). Even though these experiments suggested a role for both farnesylation and geranylgeranylation, they did not rule out the possibility that the effect of FPP was due to its conversion to GGPP and augmentation of geranylgeranylation. This is an important issue because the known Rho GTPase regulators of efferocytosis are only geranylgeranylated. Incomplete inhibition of HMG-CoA reductase could potentially allow low level synthesis of the 5-carbon isopentenyl pyrophosphate (IPP), which normally condenses with 15-carbon FPP to produce 20-carbon GGPP (Fig. 1A), thereby creating a pathway for FPP repletion to influence geranylgeranylation.
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Lovastatin suppresses membrane-bound RhoA greater than Rac-1
Statins inhibit prenylation and membrane localization of a variety of Rho GTPases, including positive (Rac-1) and negative (RhoA) regulators of efferocytosis. Yet, in HMDMs, lovastatin consistently enhanced efferocytosis, implying that lovastatin may exert a prolonged, disproportionate effect on the prenylation and membrane localization of RhoA. To address this hypothesis, HMDMs were treated with and without lovastatin for 24 h, and membrane fractions were assessed for RhoA and Rac-1 staining by Western blot. Lovastatin decreased membrane-bound RhoA greater then Rac-1 (Fig. 4, A and B), suggesting a mechanism for the positive effect of lovastatin on efferocytosis.
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We next used the potent RhoA activator, LPA to address whether lovastatin could reverse impaired efferocytosis in vitro (57). LPA-suppressed efferocytosis by HMDMs, and this suppression was prevented by lovastatin (Fig. 4C), suggesting that lovastatin, or for that matter other Rho pathway inhibitors, could play a therapeutic role in diseases where suppression of efferocytosis contributes to disease pathogenesis.
Lovastatin increases efferocytosis in vivo
We tested whether statins could enhance efferocytosis by treating mice with lovastatin (10 mg/kg) three times over 30 h. Ten million, Cell Tracker Red-labeled apoptotic murine thymocytes were then instilled intratracheally and clearance was assessed. This model has previously been used to evaluate efferocytosis by macrophages and epithelial cells in vivo (45, 50). Defective efferocytosis is suggested by either decreased uptake into alveolar macrophages (i.e., decreased PI; Fig. 5A), or by increased recovery of apoptotic cells in the bronchoalveolar lavage (Fig. 5B). Lovastatin modestly increased efferocytosis in the naive murine lung as measured by an increase in the alveolar macrophage PI (Fig. 5C) and by a decrease in the recovery of apoptotic thymocytes (Fig. 5D).
To examine whether the action of lovastatin on efferocytosis in vivo was HMG-CoA reductase dependent, mice were treated with lovastatin (10 mg/kg), three times over 30 h, in the presence or absence of rescue mevalonate, and clearance of apoptotic thymocytes by alveolar macrophages was assessed. Lovastatin again increased efferocytosis by alveolar macrophages in vivo, and this effect was prevented by mevalonate (Fig. 5E). Together, these results indicate that lovastatin enhances efferocytosis in the naive murine lung in an HMG-CoA reductase-dependent manner, thus confirming in vitro results.
Lovastatin enhances efferocytosis by human alveolar macrophages taken from patients with COPD
Accumulating evidence suggests that efferocytosis is dysregulated in chronic inflammatory lung diseases, such as COPD, and may contribute to disease pathogenesis. For example, several animal models of COPD are associated with increased accumulation (58, 59, 60, 61) and impaired removal (45) of apoptotic cells. Likewise, apoptotic cells are increased in COPD lungs (31, 62, 63, 64, 65) and efferocytosis is defective in COPD alveolar macrophages ex vivo (32). Therefore, we tested the effect of lovastatin on efferocytosis by alveolar macrophages isolated from GOLD stage 2 (66) COPD patients (Table I). Lovastatin enhanced efferocytosis in these alveolar macrophages in an HMG-CoA reductase-dependent fashion (Fig. 6). Taken together, these data suggest that statins may have therapeutic potential in diseases, such as COPD, where efferocytosis is suppressed and inflammation is dysregulated.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Up to 2% of expressed cellular proteins are prenylated and over 150 prenylated proteins have been identified (73, 74), suggesting that the effect of statins on efferocytosis is likely to be complex. Our findings indicate that lovastatin enhanced efferocytosis in vitro, in part, by altering the membrane balance of RhoA and Rac-1, two key regulators of efferocytosis. Geranylgeranyltransferase I prenylates both RhoA and Rac-1, yet lovastatin suppressed membrane localization of RhoA to a greater extent than Rac-1. The reason(s) for this disproportionate effect is unclear, but it suggests that enzyme kinetics favor prenylation of Rac-1 over RhoA. Because lovastatin increased efferocytosis after 5 days of treatment, the effect appears to be sustained. Possible explanations for this prolonged effect include: 1) geranylgeranyltransferase I may prenylate Rac-1 more efficiently than RhoA, or 2) prenylation of Rac-1 may be less substrate dependent. Even during lovastatin treatment, prenylation substrates (GGPP or FPP) would be expected to be present in small quantities due to incomplete blockade of HMG-CoA reductase, or due to salvage pathway activity (75). Alternatively, 3) the half-life of prenylated Rac-1 may be longer than prenylated RhoA. This possibility is less likely, because lovastatin enhanced efferocytosis as long as 5 days after treatment. We also noted that the ability of lovastatin to increase efferocytosis by HMDMs waned during days 3 and 4 of treatment, but increased again at day 5. We do not have a clear explanation for this observation, but it was consistent across both concentrations tested.
Our data suggest that farnesylated proteins might negatively regulate efferocytosis, because inhibition of farnesyltransferase modestly increased efferocytosis, and FPP repletion reversed lovastatin-enhanced efferocytosis. RhoB is an attractive candidate for this effect, because it is both farnesylated and geranylgeranylated (76) and it plays a known role in the phagocytosis of Pneumocystis (77). Whether farnesyltransferase inhibitors also shift the balance toward production of other geranylgeranylated proteins that could enhance efferocytosis, like Rac-1, Cdc42, or RhoG (43, 78), remains to be determined.
Growing evidence from animal models indicates that statins may have a role in the treatment of inflammatory lung diseases, including acute lung injury (2), asthma (18), and emphysema (19). Our data supports this notion, because lovastatin increased efferocytosis in the lungs of naive mice. In vivo, lovastatin may enhance efferocytosis by altering the balance of membrane-bound RhoA and Rac-1, as was demonstrated in vitro. Alternatively, in vivo and especially in an inflammatory environment, lovastatin may enhance efferocytosis by suppressing oxidative stress, because oxidative stress inhibits efferocytosis by activating RhoA (K. A. McPhillips, manuscript in preparation). Lovastatin also suppresses matrix metalloproteinase-9 (8), which inhibits efferocytosis in vitro (R. W. Vandivier, unpublished data), and is an important component of lung inflammation. Finally, statins increase PPAR, which has also been shown to increase efferocytosis (79).
Lovastatin did not enhance efferocytosis by altering apoptotic cell binding or by increasing expression of efferocytosis receptors. In contrast, Ruiz-Velasco et al. (55) found that lovastatin treatment (10 µM) increased CD36 surface expression and mRNA in human monocytes at 24 h and THP-1 cells at 48 h. The disparity between our findings may relate to intrinsic differences between human monocytes and HMDMs.
Lovastatin suppressed FcR-mediated phagocytosis in an HMG-CoA reductase-dependent manner, confirming recent reports (53, 54). Interestingly, these authors all concluded that statins suppress FcR-mediated phagocytosis by inhibiting cholesterol biosynthesis, and not by inhibiting prenylation (53, 54). Like efferocytosis, prenylated proteins like Rac-1, Cdc42, and Rab11 are required for FcR-mediated phagocytosis (80, 81), and a role for RhoA has been suggested (82). Therefore, we propose that under certain conditions statins might also influence FcR phagocytosis through modulation of Rho GTPases. The effect of statins on FcR-mediated phagocytosis is concerning because of its potential to impair host defense, but ultimately, its importance remains to be demonstrated in vivo. In a Klebsiella pneumoniae mouse model of pneumonia, lovastatin delayed bacterial clearance and enhanced dissemination (2). In contrast, statins have consistently improved survival in animal and human bacterial sepsis (16, 22, 83), implying that the beneficial effects of statins may outweigh their potential deleterious effects.
The dose and concentration of lovastatin used in the in vitro and in vivo experiments is certainly higher than is used clinically, suggesting that lovastatin may not augment efferocytosis when used in humans. In mice, however, lovastatin induces a 6- to 10-fold increase in hepatic microsomal HMG-CoA reductase after only 24 h, implying that higher doses may be required to produce clinical effects in mice compared with humans (48). In humans, prolonged administration of lovastatin at 80 mg/kg/day results in steady state concentrations ranging from 0.15 to 0.3 µM (84), which is marginally less than the lowest effective concentration of lovastatin used in our study (1 µM). The effectiveness of lovastatin in vivo, though, may depend on the clinical setting and remains to be determined in COPD. For example, it is possible that prolonged lovastatin treatment at clinically relevant doses may augment efferocytosis in humans with COPD, especially if RhoA activity is increased.
The ability of statins to enhance efferocytosis suggests a new mechanism by which statins may modulate acute and chronic inflammatory diseases, and may help direct statin clinical trials to specific diseases. For example, cystic fibrosis, bronchiectasis, and COPD are attractive targets for statin therapy because they are all associated with accumulation, and defective clearance, of apoptotic cells (31, 32). Indeed, our data provides "proof of principle" for this approach because lovastatin increased efferocytosis by human alveolar macrophages taken from patients with COPD. Lee et al. (19) have also shown that statin treatment inhibits the development of cigarette smoke-induced emphysema in rats. However, we would not suggest that potential therapeutic targets be limited to these chronic inflammatory lung diseases, because accumulation of apoptotic cells and failed efferocytosis has also been implicated in systemic inflammatory diseases, like glomerulonephritis (34), rheumatoid arthritis (36), and systemic lupus erythematosus (35).
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Disclosures |
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Footnotes |
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1 This work was supported by an Atorvastatin Research Award (to R.W.V.) sponsored by Pfizer, COPD Center funding (to K.M.), Pew Latin American Fellows Program in the Biomedical Sciences (to V.M.B.), and by grants from the National Institutes of Health to R.W.V. (HL072018) and P.M.H. (GM061031 and HL068864). 
2 Address correspondence and reprint requests to Dr. R. William Vandivier, COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, C272, Denver, CO 80220. E-mail address: Bill.Vandivier{at}uchsc.edu
3 Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor; HMG-CoA, 3-hydroxyl-3-methylglutaryl coenzyme A; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; COPD, chronic obstructive pulmonary disease; HMDM, human monocyte-derived macrophage; PI, phagocytic index; IPP, isopentenyl pyrophosphate; LPA, lysophosphatidic acid.
Received for publication December 21, 2005. Accepted for publication March 30, 2006.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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 Y. Q. Xiao, C. G. Freire-de-Lima, W. P. Schiemann, D. L. Bratton, R. W. Vandivier, and P. M. Henson Transcriptional and Translational Regulation of TGF-{beta} Production in Response to Apoptotic Cells J. Immunol., September 1, 2008; 181(5): 3575 - 3585. [Abstract] [Full Text] [PDF]
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P. M. Henson and R. M. Tuder Apoptosis in the lung: induction, clearance and detection Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L601 - L611. [Abstract] [Full Text] [PDF]
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A. Churg, M. Cosio, and J. L. Wright Mechanisms of cigarette smoke-induced COPD: insights from animal models Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L612 - L631. [Abstract] [Full Text] [PDF]
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L. M. Fabbri, F. Luppi, B. Beghe, and K. F. Rabe Complex chronic comorbidities of COPD Eur. Respir. J., January 1, 2008; 31(1): 204 - 212. [Abstract] [Full Text] [PDF]
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S. M. Bianchi, L. R. Prince, K. McPhillips, L. Allen, H. M. Marriott, G. W. Taylor, P. G. Hellewell, I. Sabroe, D. H. Dockrell, P. W. Henson, et al. Impairment of Apoptotic Cell Engulfment by Pyocyanin, a Toxic Metabolite of Pseudomonas aeruginosa Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 35 - 43. [Abstract] [Full Text] [PDF]
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 N. Minematsu and S. D. Shapiro To Live and Die in the LA (Lung Airway): Mode of Neutrophil Death and Progression of Chronic Obstructive Pulmonary Disease Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 129 - 130. [Full Text] [PDF]
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 T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]
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N. F. Voelkel, I. S. Douglas, and M. Nicolls Angiogenesis in Chronic Lung Disease Chest, March 1, 2007; 131(3): 874 - 879. [Abstract] [Full Text] [PDF]
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 D. M. Schrijvers, G. R.Y. De Meyer, A. G. Herman, and W. Martinet Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability Cardiovasc Res, February 1, 2007; 73(3): 470 - 480. [Abstract] [Full Text] [PDF]
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 A. W. Jehle, S. J. Gardai, S. Li, P. Linsel-Nitschke, K. Morimoto, W. J. Janssen, R. W. Vandivier, N. Wang, S. Greenberg, B. M. Dale, et al. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages J. Cell Biol., August 14, 2006; 174(4): 547 - 556. [Abstract] [Full Text] [PDF]
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P. M. Henson, G. P. Cosgrove, and R. W. Vandivier State of the Art. Apoptosis and Cell Homeostasis in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, August 1, 2006; 3(6): 512 - 516. [Full Text] [PDF]
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