- Open Access
Overexpression of sICAM-1 in the Alveolar Epithelial Space Results in an Exaggerated Inflammatory Response and Early Death in Gram Negative Pneumonia
© Mendez et al; licensee BioMed Central Ltd. 2011
- Received: 20 April 2010
- Accepted: 19 January 2011
- Published: 1 December 2011
A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM-1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection.
Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM-1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae.
SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM-1 mice compared with wild-type mice but there were no difference in lung CFU between groups.
We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.
- Alveolar Macrophage
- Alveolar Epithelial Cell
- Alveolar Space
- Distal Lung
- Lung Burden
Intercellular adhesion molecule-1 (ICAM-1) is an ~100 kDa molecule belonging to the immunoglobulin supergene family. The membrane bound form of this protein (mICAM-1) serves as a counter-receptor for the β2 integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), found on leukocytes. Interactions with mICAM-1 facilitate leukocyte transmigration across the endothelium  and over the surface of alveolar epithelial cells (AECs) in the lung . Studies using gene-targeted mice lacking ICAM-1 or neutralizing antibodies have indicated that ICAM-1 is necessary for normal pulmonary host defense [3–5]. A soluble form of the molecule, soluble intercellular adhesion molecule-1 (sICAM-1), is found in serum and in the alveolar lining fluid [6–8]. sICAM-1 in the alveolar space is likely generated by proteolytic cleavage of mICAM-1 found on type I alveolar epithelial cells .
sICAM-1 is normally present in the alveolar lining fluid of both humans and mice [6, 7, 10–13]. Like mICAM-1, sICAM-1 binds to LFA-1/Mac-1 and not only competes with leukocyte binding to mICAM-1 , but also stimulates leukocyte cytokine production . We have previously demonstrated that isolated alveolar epithelial cells (AECs), which express features of the type I cell phenotype, release sICAM-1 in primary culture . However, little is known regarding the physiologic significance of sICAM-1 in the alveolus. Because sICAM-1 is abundant in the alveolar lining fluid, and modulates both leukocyte adhesion and stimulation, sICAM-1 may modulate AEC-leukocyte interactions in the alveolus, and thus play an important role in lung diseases characterized by alveolar inflammation, such as pneumonia and acute lung injury.
Based on these considerations, we hypothesized that overexpression of sICAM-1 in the alveolus would modulate the innate immune response during acute lung inflammation and infection in mice. To address this hypothesis, we designed and characterized a genetically modified mouse that overexpresses sICAM-1 in the alveolus under control of the surfactant protein C promoter (SPC-sICAM-1). We evaluated this mouse using an established model of pulmonary infection with K. pneumoniae, comparing survival, cellular accumulation and recruitment, and alveolar macrophage (AM) function in SPC-sICAM-1 and wild-type mice. SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice, but no change in the burden of organisms within the lung. We also found that SPC-sICAM-1 mice demonstrated exaggerated inflammatory responses compared with wild-type mice. One potential mechanism underlying these differences is sICAM-1's ability to prime alveolar macrophages for elaboration of cytokines in response to LPS.
Pathogen-free wild-type C57BL/6 mice were obtained from Jackson Laboratories (Bar Harbor, ME) at 6-12 weeks of age. All animals were housed in isolator cages within the Animal Care Facilities at the Ann Arbor Department of Veterans Affairs Research Laboratories. Mice received food and water ad libitum. The experimental protocols were approved by the animal care committees at the University of Michigan and the Veterans Affairs Medical Center.
Transgenic Mouse Design
Characterization of SPC-sICAM-1 mice
Mice containing the transgene were identified by polymerase chain reaction (PCR). The forward primer was designed specific to the transcription start site of the SPC gene, 5'-CATATAAGACCCTGGTCACACCTGGGAGA-3', and the reverse primer, 5'-TGTGCGGCATGAGAAATTGGCTCCGTGGTC-3', was designed specific to the ICAM-1 cDNA region (product size 687 bp). A PCR primer directed to the endogenous mouse cholecystokinin gene was used as an internal control (forward: 5'-CTGGTTAGAAGAGAGATGAGCTACAAAGGC-3', reverse: 5'-TAGGACTGCCATCACCACGCACAGACATAC-3'; product size 361 bp). The PCR conditions were the same for each primer pair: 92°C for 2 minutes then 94°C for 30 seconds followed by annealing at 65°C for 30 seconds followed by elongation at 72°C for 45 seconds. The latter three steps were repeated for 34 cycles. The reaction was completed at 72°C for 5 minutes. PCR product sizes were analyzed by electrophoresis on a 2.2% FlashGel DNA cassette (Lonza, Rockland, ME) using the FlashGel system (Lonza). Confirmation of lung specific expression was performed by isolating total RNA from lung, spleen, heart, liver, and kidney using the Absolutely RNA Miniprep Kit (Strategene, La Jolla, CA) following the manufacturer's instructions. The purified RNA was subjected to reverse transcriptase PCR with primers specific for the proSPC-sICAM-1 message (forward primer: 5'-ACCTGCAGGTCGACTCTAGAGGATCCC-3'; reverse primer: 5'- TGTGCGGCATGAGAAATTGGCTCCGTGGTC-3'; product size 637 bp; Figure 1a). The real time PCR reaction conditions were as follows: 55°C for 40 minutes, then 95°C for 10 minutes, followed by 95°C for 30 seconds, 60°C for 1 minutes, and 72°C for 30 seconds. The latter three steps were repeated for 34 cycles. The resultant product was then analyzed by electrophoresis on a 2.2% Lonza gel.
Processing of bronchoalveolar lavage fluid for Western analysis
BAL was performed in transgenic mice and control mice using previously described methods . BAL was performed using five 1-ml aliquots of PBS that were pooled. Typical return was 90-95% of instilled volume. BAL fluid was centrifuged at 500 × g for 10 minutes at 4°C to remove whole cells. Diluted proteins from BAL were concentrated using a 100 kD molecular weight cut off centrifugal filter (Millipore). Supernatants were stored at -70°C for subsequent analysis of sICAM-1 by Western Blot.
Western analysis of sICAM-1
The samples were denatured in sample buffer [2% sodium dodecyl sulfate (SDS), 10% glycerol, 62.5 mM Tris HCl, pH 6.8] at 100°C and separated by SDS-polyacrylamide gel electrophoresis (PAGE) (10% acrylamide) under non-reducing conditions, loading 20 μg of protein in each lane. After PAGE, the separated proteins were electrophoretically-transferred to PVDF membrane (Bio-Rad Laboratories, Richmond, CA). Full range protein molecular weight standards were purchased from Bio-Rad Laboratories. The PVDF membranes were incubated in 5% bovine serum albumin to block nonspecific binding and exposed to rat mAb AB796 (R&D Systems, specific for the extracellular domain of mouse ICAM-1), or control rat IgG2b antibody (R&D Systems). The membranes were then incubated with anti-rat secondary antibody conjugated to horseradish peroxidase (Jackson ImmunoResearch Laboratories, West Grove, PA). The membranes were washed extensively in Tris-buffered saline after each step. Subsequently, the blots were developed using a chemiluminescence system (ECL Western Blotting detection system, Amersham, Arlington Heights, IL) according to the manufacturer's recommendations.
BAL serum and lung homogenates from mice from experimental and control groups were analyzed for total sICAM-1 levels by commercially available ELISA kits (R&D Systems, Minneapolis, MN). The absorbance was measured at 450 nm by a microplate autoreader (BioTek, Winooski, VT), with a correction wavelength set at 570 nm. All measurements were preformed following the manufacturer's instructions, and the final concentrations were calculated by reference to the standard curves.
Preparation of Klebsiella pneumoniae
K. pneumoniae strain 43816, serotype 2 was obtained from American Type Culture Collection (ATCC, Manassas, VA). K. pneumoniae was grown overnight with aeration in 25 ml of LB broth (Invitrogen, San Diego, CA), at 37°C on a shaker at 300 rpm. The culture was diluted 1:20 and grown for 45 min at 37°C until it reached 0.1 nm OD. Bacteria were then diluted in sterile phosphate-buffered saline (PBS) to the appropriate CFU/ml (2500 or 250 CFU/100 μl) for intranasal inoculation. Bacteria were maintained on ice until inoculation.
Inoculation of mice with K. pneumoniae
Twelve week old transgenic mice and wild-type mice were anesthetized with inhaled isofluorane and inoculated intranasally with 100 μl of the K. pneumoniae suspension. Appropriate dilutions of the inocula were plated on LB agar plates to confirm the doses administered. Other groups of mice were not exposed to K. pneumoniae, but were inoculated with 100 μl of PBS as negative controls.
Lung harvest for histological examination
At 24 hours post-inoculation, one mouse from each group was euthanized for lung histology. The lungs were perfused via the right ventricle with DPBS to remove excess blood and inflated with formaldehyde to improve resolution. The lungs and central airways were then removed en bloc and fixed in formaldehyde. After removing the central airways, the lungs were transferred to histocassettes (Fischer Scientific), incubated in formaldehyde, embedded in paraffin and processed for sectioning and staining.
Determination of lung CFU and dissemination of K. pneumoniae
In order to assess the burden of organisms with the lungs, mice were inoculated with K. pneumoniae (2500 CFU in100 μl) and euthanized after 24 hours. The pulmonary vascular bed was perfused via the right ventricle with DPBS. Lungs and spleen were removed using sterile technique, and collected in 1 ml and 0.5 ml of 2× Complete Buffer (Roche, Nutley, NJ), respectively. The tissues were then homogenized with an Ultra-Turrax T8 Homogenizer (IKA-Labortechnik, Germany). Aliquots from lungs and spleens were serially diluted in DPBS to 10-9. 10 μl of each dilution was plated on LB agar plates (Invitrogen) and incubated at 37°C. Colony counts for each animal were determined after 24 hours. A priori, we defined positive spleen cultures to be > 10 CFU of K. pneumoniae.
Phagocytosis of fluorescent beads by AM
Mice were inoculated intranasally with 100 μl of 5 × 107 of FITC-labeled bioparticles (pHrodo Bioparticles Conjugates, Invitrogen). Control mice were inoculated with DPBS. One hour post-inoculation, four mice from each group were euthanized and BAL was obtained as described . Fluorescence intensity of each sample was measured by flow cytometry, using a FACScan cytometer (Becton Dickinson, Mountain View, CA) with CellQuest software. A minimum of 10,000 viable cells was analyzed per sample.
Differential cell counts in total lung lavage by flow cytometry
Perfused lungs were lavaged with10 ml of Dulbecco's PBS with mM EDTA. Cells were washed with PBS and resuspended at 1 × 106 cells per ml of PBS. Before addition of antibodies, the samples were prepared with a Live/Dead Fixable Aqua Dead Cell Strain Kit (Invitrogen, San Diego, CA). Fc Block was added to all samples following the manufacturer's instructions to reduce non-specific binding of antibodies to the activated cells. For analysis by flow cytometry, the samples were washed twice in staining buffer (Difco, Detroit, MI), resuspended in staining buffer, and incubated for 30 min at 4°C in the dark with labeled antibodies. The following antibodies were obtained from BD: 1A8 (antimurine Ly-6G; FITC-conjugated) was used to gate on PMN; M1/70 (antimurine CD11b, PerCP-Cy5.5-conjugated) was used to gate on monocytes; and 30-F11 (antimurine CD45; APC-Cy7-conjugated) was used to gate on all leukocytes. The following antibodies were obtained from eBioscience (San Diego, CA): MTS510 (antimurine TLR4; PE-conjugated), N418 (antimurine CD11c; Pacific Blue) was used to gate on mature alveolar macrophages; and HI30 (antimurine CD45; Pacific Blue) was used to gate on all leukocytes. Appropriate isotype-matched controls were used in all experiments. All samples were analyzed on the BD LSR II flow cytometer with 3 lasers (488 nm blue, 405 nm violet, and 633 nm HeNe red). A minimum of 10,000 viable cells was analyzed per sample, first gating on CD45+ cells and second gating on live cells using the Live/Dead Fixable Aqua Dead Cell Strain Kit. Gating on specific leukocytes populations was performed using antibodies described above. Absolute numbers of each subset were determined by multiplying the total cell count by hemacytometer with percentage results from flow cytometry. Data were collected using FACS Diva software with automatic compensation and were analyzed using FlowJo software.
In vitro stimulation of AM with LPS and recombinant sICAM-1
AM were isolated from wild type C57BL/6 mice by bronchoalveolar lavage with PBS. The AM were plated at a concentration of 100,000 cells/well and allowed to adhere in a 96-well plate for one hour. Cells were incubated individually or in combination with Polymixin B Sulfate (Sigma Aldrich) (50 μg/ml), recombinant sICAM-1 (Stem Cell Technologies) (50 μg/ml), and/or LPS (Escherichia coli-derived; Sigma Aldrich) (1 μg/ml). Samples were incubated for 24 hours. All incubations were performed at 37°C and 5% CO2. After the incubation, the media was recovered and the supernatants were analyzed by commercially available ELISA kits (R&D Systems, Minneapolis, MN) for MIP2, KC, and TNF-α. The addition of Polymixin B had no effect on cytokine expression induced by sICAM-1 alone, suggesting that recombinant sICAM-1 was not contaminated with LPS (data not shown).
Data are expressed as means with standard error of the mean represented by error bars. The data were compared using a two-tailed Student's t-test or a Chi square contingency table. If more than two groups were compared an ANOVA was used. Survival difference between groups was analyzed using Kaplan-Meier curves and Log-rank (Mantel-Cox) Test. Differences were considered statistically significant if p values were < 0.05. All statistical analysis was performed with the GraphPad Prism 5 package from GraphPad Software (San Diego, CA).
SPC-sICAM-1 transgenic mice overexpress sICAM-1 in the lung
A western blot of BALF protein from transgenic versus wild-type mice using an anti-ICAM-1 antibody specific to the external domain of mICAM-1 demonstrated a unique100 kDA band (transgene product, black arrowhead Figure 2e) in the transgenic mice, not present in the wild type mice. A slightly lower molecular weight band representing endogenous sICAM-1 was present in both SPC-sICAM-1 transgenic and wild-type mice (white arrowhead Figure 2e). We have previously shown that production of sICAM-1 in the alveolar space of wild-type mice is likely mediated by proteolytic cleavage of mICAM-1 on the surface of type I AEC . In addition to proteolytic-mediated production of sICAM-1, SPC-sICAM-1 mice also generate sICAM-1 through direct release of the transgene protein from type 2 AEC. The transgenic sICAM-1 lacks membrane and cytoplasmic domains and thus is directly released from the cell.
SPC-sICAM-1 mice have decreased survival compared to wild-type mice after K. pneumoniae infection
SPC-sICAM-1 mice infected with K. pneumoniae demonstrate increased systemic dissemination compared to wild-type mice
SPC-sICAM-1 mice infected with K. pneumoniae have increased cellular recruitment compared to wild-type mice
To determine a potential mechanism explaining the increased number of acute inflammatory cells in SPC-sICAM-1 mice, we measured chemokines in BAL fluid at 24 hrs. MIP2 and KC were increased in SPC-ICAM-1 mice, although the difference was not statistically significant (54.0 ± 28.8 pg/ml vs 16.5 ± 6.9 pg/ml and 107.8 ± 45.1 pg/ml vs 32.2 ± 7.5 pg/ml, respectively). Thus, high level expression of sICAM-1 in the distal lungs results in increased cellular recruitment in the lung after infection with K. pneumoniae.
SPC-sICAM-1 alveolar macrophage phagocytosis is not impaired compared to wild-type mice
AM incubated with sICAM-1 and LPS in vitro results in synergistic production of TNFα and MIP2
SPC-sICAM-1 mice infected with K. pneumoniae demonstrate a trend toward increased alveolar leak
In these studies, we evaluated the effect of lung targeted expression of sICAM-1 in the alveolar space in the context of Gram negative pneumonia. There are several key findings. First, high levels of sICAM-1 in the alveolus increased mortality after K. pneumonia infection. Second, this increased mortality was associated with increased systemic dissemination of organisms, without change in the burden of organisms within the lung. Third, high levels of sICAM-1 in the alveolus did not affect AM number, phenotype or phagocytic function. Fourth, high levels of sICAM-1 in the alveolus resulted in enhanced cellular recruitment of acute inflammatory cells to the lung after K. pneumonia infection. Finally, sICAM-1 and LPS interact synergistically to increase cytokine elaboration by AMs. Taken together, these findings imply a significant, unique role for sICAM-1 in modulating the inflammatory response to alveolar infections.
In this study, we used transgenic technology to direct expression of the sICAM-1 molecule to the alveolus using the human SPC promoter. The 3.7 kB human SPC promoter has been used successfully to drive expression of GM-CSF in a mouse deficient in GM-CSF to correct the condition of pulmonary alveolar proteinosis in the deficient mice . Others have used the human SPC promoter to direct expression human alpha-1 antitrypsin to the alveolus to assess development of emphysema in a smoking mouse model . We used the same promoter to drive expression of a truncated form of mICAM-1 in the lung. The founder line that was selected for study was morphologically and behaviorally indistinguishable from the wild-type litter mate controls. This founder was specifically chosen due to its high level of sICAM-1 expression found in the BALF compared to wild-type mice (100-fold increase). BALF protein examined by Western Blot demonstrated a discrete band at apparent molecular weight (~100 kD) that was nearly the same as that of mICAM-1 (~105 kDA). The size of endogenous sICAM-1 is ~90 kDA [7, 23]. We have previously shown that endogenous sICAM-1 in the alveolus is most likely proteolytically cleaved from mICAM-1 on the surface of type I AEC . ICAM-1 is heavily glycosylated and its apparent molecular weight can vary . Because sequencing confirmed that the transgene actually lacked the intracellular and transmembrane portions of ICAM-1(data not shown), it is most likely that the increased apparent molecular weight of transgenic sICAM-1 is a result of post-translational processing, such as differential glycosylation.
These experiments demonstrate that alveolar sICAM-1 overexpression alters the response to infection. Until now, much of the focus on ICAM-1 in lung inflammation has been related to the membrane-bound form and its role in leukocyte trafficking [4, 5, 25, 26]. mICAM-1 and sICAM-1 are expressed and regulated uniquely by type I AEC . Therefore, we hypothesized that alteration in the amount of sICAM-1 in the alveolus would alter the inflammatory response. Our results demonstrate that excess sICAM-1 in the alveolus in the setting of K. pneumoniae infection results in decreased survival. It is possible this effect on mortality might be a result of inhibition of AM-AEC interactions mediated by mICAM-1 due to blockade of AM cell surface ligands by the high levels of sICAM-1. Thus sICAM-1 might be playing a role similar to that of other soluble receptors such as syndecans or receptor for advanced glycation end products (RAGE) [27, 28]. However, overexpression of sICAM-1 results in a response that differs in significant ways from that found either in ICAM-1 deficient mice or with antibody-mediated neutralization of ICAM-1 in the lung [4, 5]. In contrast to the circumstance in ICAM-1 deficient mice, neither the burden of organisms in the lung nor the ability of AM to phagocytose FITC-labeled beads in vivo was altered by overexpression of sICAM-1. However, despite similar numbers of organisms in the lung, inflammatory cell recruitment was in fact increased in SPC-sICAM-1 mice compared to wild-type mice. One may speculate that subtle impairment of AM activity results in excessive inflammation, which in turn contributes to lung injury, impaired barrier function, and increased systemic dissemination of infection. Our findings highlight the delicate balance required in the lung to both protect from infectious insults and preserve functional barrier to the outside world.
The mechanism(s) of decreased survival in the SPC-sICAM-1 mice in the setting of K. pneumoniae are likely complex and related to more than one factor. In our previous work, mICAM-1 deficient mice infected with K. pneumoniae also had decreased survival . We demonstrated that bacterial phagocytosis and killing by AM and neutrophils was enhanced by the interaction with mICAM-1 on AEC. We attributed the decreased survival in the ICAM-1 deficient mice to the loss of mICAM-1-mediated interactions between AEC and AM that promote AM lateral migration, phagocytosis and bacterial killing. It is possible that, in mice overexpressing sICAM-1 in the lung, competitive binding of sICAM-1 to the normal counter receptors of mICAM-1 on AM, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), prevents this important interaction. Interestingly, in the present study we found that supraphysiologic sICAM-1 does not impair AM phagocytosis of fluorescent beads in vivo, suggesting that lateral mobility and phagocytic activity of AM remain largely intact in these mice. This preservation of AM phagocytosis may reflect incomplete blockade of mICAM-1-mediated effects by sICAM-1. Despite relatively normal phagocytosis by AM, the efficiency of bacterial killing in vivo is affected. At 24 hours, there is no significant difference in burden of K. pneumoniae between SPC-sICAM-1 and wild type mice, but there is increased accumulation of acute inflammatory cells, including neutrophils, in the lungs of SPC-sICAM-1 mice compared to wild-type mice at 24 hours. Thus the efficiency of bacterial clearance is decreased in the SPC-sICAM-1 mice. We postulate that this enhanced inflammation, coupled with increased TNF-α production by alveolar macrophages, ultimately leads to increased systemic dissemination of infection.
One limitation of our transgenic design is that sICAM-1 is constitutively produced by type II AEC. Thus, the endogenous mechanisms regulating shedding of sICAM-1 form type I AEC become minimized. In this setting, overexpression of sICAM-1 may overwhelm the host's ability to modulate local levels of sICAM-1. This may lead to unchecked activation and subsequently exaggerated inflammation that may be the cause of the decreased survival we observed in the K. pneumonia infection.
Previous studies examining the role of ICAM-1 in lung inflammation have focused on the role of ICAM-1 in recruitment of leukocytes and the use of ICAM-1 blocking antibodies or ICAM-1 deficient mice. What has not been addressed is whether there are differential effects of mICAM-1 and sICAM-1 on the inflammatory cascade. In experiments designed to block ICAM-1, it is likely that both mICAM-1 and sICAM-1 being blocked [4, 5, 25, 26]. If sICAM-1 is functionally active, it is important to understand how to contrast its effects on leukocytes with the effects of mICAM-1. In studies using ICAM-1 deficient or mutant mice, the goal has generally been to study a mouse deficient in mICAM-1. However, in some instances, transgenic mice deficient in normal mICAM-1 are still capable of expressing sICAM-1, possibly through alternative splicing and subsequent cleavage . In order to separate the roles of mICAM-1 and or sICAM-1 in the alveolar or vascular compartments, it may be necessary to reintroduce either sICAM-1 or a 'noncleavable' membranous ICAM-1 into ICAM-1 knockout mice.
In summary, our study shows that overexpression of sICAM-1 in the alveolus has a major impact upon host defense in the setting of K. pneumoniae infection. In combination with previous data, our data demonstrate that sICAM-1 has functional effects that influence cellular recruitment and AM activation in the setting of acute infection. This suggests that an appropriate balance of ICAM-1 with an optimal amount of local sICAM-1 in the alveolus may be critical for optimal AM function, activation, and leukocyte recruitment.
We acknowledge Wanda Flipiak and Thom Saunders for preparation of transgenic mice and the Transgenic Animal Model Core of the University of Michigan's Biomedical Research Core Facilities. The authors gratefully acknowledge the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (Grant 085P1000815).
This work was supported by grants from the Department of Veterans Affairs (Career Development Award to MPM, Merit to RP, and Ann Arbor VA REAP) and the NHLBI (HL083844-01 to PJC).
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