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* Division of Pulmonary and Critical Care Medicine and
Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
Department of Respiratory Medicine, St Vincent’s Hospital, University College, Dublin, Ireland; and
Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98108
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our laboratory has shown that members of the CXC chemokine
family exert disparate effects in mediating angiogenesis as a function
of the presence or absence of three amino acid residues (Glu-Leu-Arg;
the "ELR motif") that immediately precedes the first cysteine amino
acid of the primary structure of these cytokines (12, 13).
Epithelial neutrophil-activating protein 78 (ENA-78)/CXC ligand (CXCL)
5, growth-related oncogene (GRO) 
/CXCL1, and IL-8/CXCL8 all contain
the ELR motif, which confers potent angiogenic activity, whereas
members such as IFN-
-inducible protein 10 (IP-10)/CXCL10 and
monokine induced by IFN- (MIG)/CXCL9 that lack the ELR motif inhibit
angiogenesis. We hypothesized that the pathogenesis of DAD with
pulmonary microvascular remodeling and alveolar fibrosis is due, in
part, to dysregulated angiogenesis, with overexpression of angiogenic
and down-regulation of angiostatic CXC chemokines. In this study, we
measured ELR+ CXC chemokines (IL-8/CXCL8,
ENA-78/CXCL5, and GRO-/CXCL1), ELR- CXC
chemokines (IP-10/CXCL10 and MIG/CXCL9), and vascular endothelial
growth factor (VEGF) by specific ELISA. ELR+ CXC
chemokines were significantly greater than ELR-
CXC chemokines from BALF of ARDS patients as compared with the control
group. Furthermore, these levels correlated with both procollagen III
and procollagen I levels in the bronchoalveolar lavage fluid (BALF) of
these patients. CXC chemokines appeared to contribute to the majority,
if not all, of the angiogenic activity in the ARDS specimens. These
findings support the notion that ELR+ CXC
chemokines have an important role in the fibroproliferative phase of
ARDS via the regulation of angiogenesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bronchoalveolar lavage was obtained from five patients with recent onset (3–5 days) ARDS and four mechanically ventilated control patients. Bronchoalveolar lavage was performed as previously described (14). BALF recovery was >50% of the instilled volume. ARDS was defined according to the American European consensus conference guidelines (15, 16). The controls had no evidence of lung disease and were being ventilated for reasons other than respiratory failure. Lung tissue specimens for immunohistochemistry were obtained from postmortem specimens of patients that had died with ARDS. Appropriate Institutional Review Board approval and informed consent was obtained.
Reagents
Polyclonal anti-human IL-8/CXCL8, GRO-/CXCL1,
ENA-78/CXCL5, IP-10/CXCL10, MIG/CXCL9, CXCR2, and VEGF Abs and human
IL-8/CXCL8, GRO-/CXCL1, ENA-78/CXCL5, IP-10/CXCL10, MIG/CXCL9, and
VEGF were purchased from R&D Systems (Minneapolis, MN). The specificity
of the Abs was assessed by Western blot analysis and ELISA against a
panel of other recombinant cytokines. Abs were specific in our sandwich
ELISA without cross-reactivity to a panel of cytokines, including
IL-1R antagonist protein, IL-1, IL-2, IL-4, IL-6, TNF-,
IFN-, and other members of the CXC and CC chemokine families
(17, 18). The "anti-protease" buffer for tissue
homogenization consisted of 1x PBS with one Complete tablet
(Boehringer Mannheim, Indianapolis, IN) per 50 ml. Rabbit
anti-factor VIII-related Ag Abs were purchased from Biomedia
(Foster City, CA).
ELISA
Antigenic human IL-8/CXCL8, GRO-/CXCL1, ENA-78/CXCL5,
IP-10/CXCL10, MIG/CXCL9, VEGF, and procollagen I were quantitated using
a modification of an ELISA as previously described (17, 18). The sensitivity of our ELISAs are 
50 pg/ml. Briefly,
flat-bottom 96-well microtiter plates (Nunc, Roskilde, Denmark) were
coated with 50 µl/well of the appropriate polyclonal Ab (1 ng/µl in
0.6 M NaCl, 0.26 M H3B04,
and 0.08 N NaOH (pH 9.6)) for 24 h at 4°C and then washed with
PBS and 0.05% Tween 20 (wash buffer). Nonspecific binding sites were
blocked with 2% BSA. Plates were rinsed and samples were added (50
µl/well), followed by incubation for 1 h at 37°C. Plates were
then washed and 50 µl/well of the appropriate biotinylated polyclonal
Ab (3.5 ng/µl in wash buffer and 2% FCS) was added for 45 min at
37°C. Plates were washed three times, streptavidin-peroxidase
conjugate (Bio-Rad, Richmond, CA) was added, and the plates were
incubated for 30 min at 37°C. Chromogen substrate (DAKO, Carpinteria,
CA) was then added, and the plates were incubated at room temperature
to the desired extinction. Plates were read at 490 nm in an automated
microplate reader (Bio-Tek Instruments, Winooski, VT). Standards were
1/2 log dilutions of recombinant cytokine from 100 ng to 1 pg/ml (50
µl/well).
Procollagen III assay
Procollagen III was measured by a RIA using a modification of a method as previously described (19, 20). Briefly, concentrations of procollagen III peptide (PIIIP) in BALF samples were measured by RIA using RIA-gnost PIIIP (CIS Biointernational, Gif-Sur-Yvette, France) according to the manufacturer’s instructions, as previously described (19). BALF samples (undiluted) were measured in duplicate, and samples were further diluted as needed to allow interpolation of PIIIP values from simultaneously generated standard curves.
Immunohistochemistry for IL-8/CXCL8, ENA-78/CXCL5,
GRO-/CXCL1, and CXCR2
Paraffin-embedded tissue from control and idiopathic pulmonary
fibrosis (IPF) lung was processed for immunohistochemical localization
of IL-8/CXCL8, ENA-78/CXCL5, GRO-/CXCL1, and CXCR2. Briefly, tissue
sections were dewaxed with xylene and rehydrated through graded
concentrations of ethanol. Tissue-nonspecific binding sites were
blocked using normal goat serum (BioGenex, San Ramon, CA). Tissue
sections were then washed and overlaid with a 1/500 dilution of either
control (rabbit) or polyclonal rabbit Abs to the appropriate chemokine
or receptor. The tissue sections were washed and then incubated for 60
min with secondary goat anti-rabbit biotinylated Abs (BioGenex).
After washing twice with TBS, slides were overlaid with a 1/35 dilution
of peroxidase conjugated to streptavidin (Vector Laboratories,
Burlingame, CA) and incubated for 60 min. Tissue sections were then
incubated with Vectastain avidin-biotin complex reagent (Vector
Laboratories) followed by the peroxidase substrate diaminobenzidine
reagent (Vector Laboratories). After optimal color development, tissue
sections were immersed in sterile water, counterstained with Mayer’s
hematoxylin, and coverslipped using an aqueous mounting solution.
Immunolocalization of factor VIII-related Ag
Paraffin-embedded ARDS lung tissue was processed for immunohistochemical localization of factor VIII-related Ag as previously described (21). Briefly, tissue sections were dewaxed with xylene and rehydrated through graded concentrations of ethanol. Slides were blocked with normal rabbit serum (BioGenex) and overlaid with a 1/500 dilution of either control (goat) or goat anti-factor VIII-related Ag Abs. Slides were then rinsed and overlaid with secondary biotinylated rabbit anti-goat IgG (1/35) and incubated for 60 min. After washing twice with TBS, slides were overlaid with a 1/35 dilution of peroxidase conjugated to streptavidin (Vector Laboratories) and incubated for 60 min. Tissue sections were then incubated with Vectastain avidin-biotin complex reagent (Vector Laboratories) followed by the peroxidase substrate diaminobenzidine reagent (Vector Laboratories). After optimal color development, tissue sections were immersed in sterile water, counterstained with Lerner’s hematoxylin, and coverslipped using an aqueous mounting solution.
Corneal micropocket assay of angiogenesis
Angiogenic activity of BALF was assayed in vivo in the avascular cornea of hooded Long-Evans rat eyes, as previously described (12, 17, 18, 21, 22, 23). Briefly, equal volumes of BALF normalized to total protein were combined with sterile Hydron (Interferon Sciences, New Brunswick, NJ) casting solution. Five-microliter aliquots were pipetted onto the flat surface of an inverted sterile polypropylene specimen container and polymerized overnight in a laminar flow hood under UV light. Before implantation, pellets were rehydrated with normal saline. Animals were anesthetized with ketamine (150 mg/kg) and atropine (250 µg/kg) i.p. Rat corneas were anesthetized with 0.5% proparacaine hydrochloride ophthalmic solution followed by implantation of the Hydron pellet into an intracorneal pocket (1–2 mm from the limbus). Six days after implantation, animals received 1000 U of heparin and ketamine (150 mg/kg) i.p., followed by a 10-ml perfusion of colloidal carbon via the left ventricle. Corneas were harvested and photographed. No inflammatory response was observed in any of the corneas treated with the above specimens. Positive neovascularization responses were recorded only if sustained directional ingrowth of capillary sprouts and hairpin loops toward the implant were observed. Negative responses were recorded when either no growth was observed or when only an occasional sprout or hairpin loop displaying no evidence of sustained growth was detected. All animals were handled in accordance with the Department of Laboratory Animal Medicine at the University of California, Los Angeles.
Statistical analysis
Data were analyzed on a Dell PC computer using the Statview 4.5 statistical package (Abacus Concepts, Berkeley, CA). ELISA data were compared using the nonparametric Mann-Whitney U test. A p of 0.05 or less was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies have indicated the presence of vascular
remodeling in ARDS (3, 24). On this basis, we assessed the
presence of vascular remodeling in ARDS. We confirmed the presence of
angiogenic activity by demonstrating significant vascular remodeling in
ARDS lung tissue specimens as evidenced by the immunolocalization of
factor VIII-related Ag (Fig. 1
, C and D). Similarly, CXCR2, the receptor for
ELR+CXC chemokines was localized predominantly to
vascular endothelium (Fig. 1B). Furthermore, using the
corneal micropocket assay we found that pooled samples of ARDS BALF
(Fig. 2B) induced a greater
angiogenic response, as compared with ventilator control BALF (Fig. 2A; n = 6 for each manipulation).
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We obtained BALF from patients with either ARDS (n
= 5) or patients who were being ventilated for reasons other than
respiratory failure (control BALF; n = 4) and measured
procollagen III and I levels by specific ELISA and RIA, respectively.
BALF from ARDS patients, as compared with control BALF, demonstrated
greater levels of procollagen I (25.72 ± 14.65 ng/ml vs 0 ±
0 ng/ml) and procollagen III (1.176 ± 0.65 U/ml vs 0.3 ± 0
U/ml) (p < 0.05; Fig. 3)
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We obtained BALF from patients with either recent onset ARDS (days
3–5; n = 5) or patients who were being ventilated for
reasons other than respiratory failure (control BALF; n
= 4) and measured IL-8/CXCL8, ENA-78/CXCL5, GRO-/CXCL1,
IP-10/CXCL10, and MIG/CXCL9 by specific ELISA. BALF from ARDS patients
demonstrated a significant increase in neutrophils as compared with
controls (p < 0.05; Table I). BALF from ARDS patients, as compared
with control BALF, demonstrated greater levels of IL-8/CXCL8 (1.22
± 0.76 ng/ml vs 0 ± 0 ng/ml), ENA-78/CXCL5 (1.77 ± 0.54
ng/ml vs 0.1 ± 0.09 ng/ml), and GRO-/CXCL1 (10.87 ± 3.73
ng/ml vs 0.1 ± 0.1 pg/ml) (p < 0.05;
Fig. 4). In contrast, BALF from ARDS
demonstrated equivalent levels of IP-10/CXCL10 (0.48 ± 0.38 ng/ml
vs 0.49 ± 0.05 ng/ml) (p = NS). Levels of
MIG/CXCL9 (1.48 ± 0.93 ng/ml vs 0.21 ± 0.039 ng/ml;
p < 0.05) were elevated as compared with control BALF
(Fig. 5). The ratio of
ELR+ to ELR- CXC
chemokines favored ELR+ CXC chemokines and net
angiogenic activity (Table II). We also
measured levels of VEGF and found that BALF from ARDS patients, as
compared with control BALF, demonstrated greater levels of VEGF,
although not to the same magnitude as the CXC chemokines (0.15 ±
0.06 pg/ml vs 0.0 ± 0.0 pg/ml) (p = 0.05;
Fig. 4).
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The histopathology of ARDS is characterized by inflammatory
infiltrates. Since IL-8, ENA-78, and GRO- were elevated in BALF, we
next assessed the predominant cellular source of these chemokines in
ARDS lung tissue. Using immunohistochemistry, we found that the
predominant cells in ARDS lung tissue that expressed IL-8 and ENA-78
were macrophages (Fig. 6). The
predominant cells expressing GRO- were macrophages and also
endothelial and epithelial cells (Fig. 6). In contrast, the predominant
cells expressing CXCR2 were vascular endothelial cells (Fig. 1
B).
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To substantiate that these CXC chemokines may be modulating lung
tissue-derived angiogenic activity, we next assessed the in vivo
angiogenic activity of random pooled samples of either control
(n = 4) or ARDS BALF (n = 5) in the
presence or absence of preimmune (control) or neutralizing CXCR2 Abs,
using the rat corneal micropocket model of neovascularization (Fig. 7 and Table III). CXCR2 is the major receptor for all
of the ELR+ CXC chemokines. These Abs did not
contain significant quantities of LPS contamination as assessed by
Limulus assay, and all samples were normalized to total
protein. Neutralizing Abs to CXCR2 significantly attenuated the
angiogenic activity of ARDS BALF (1 of 6 positive; Fig. 7 and Table III), as compared with control Abs (6 of 6 positive; Fig. 7 and Table III) (n = 6 for each manipulation). These findings
suggest that the ELR+ CXC chemokines are
significant angiogenic factors in ARDS.
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Since VEGF has been shown to be an important angiogenic factor and
has been implicated in acute lung injury, we assessed the contribution
of VEGF to BALF-derived angiogenic activity. We assessed the in vivo
angiogenic activity of random pooled samples of either control
(n = 4) or ARDS BALF (n = 5) in the
presence or absence of control or neutralizing VEGF Abs, using the rat
cornea micropocket model of neovascularization (Fig. 7 and Table II).
We confirmed the neutralizing capacity of these Abs using the corneal
micropocket model. These Abs did not contain significant quantities of
LPS contamination as assessed by Limulus assay, and all
samples were normalized to total protein. Neutralizing Abs to VEGF did
not significantly attenuate the angiogenic activity of ARDS BALF (4 of
6 corneas positive) as compared with control Abs (6 of 6 positive).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We found elevated levels of both procollagen III and I in patients with ARDS. This is consistent with previous work, which has demonstrated elevated levels of procollagen III in both ARDS pulmonary edema fluid and BALF as early as 24 h after injury (20, 34). Elevated levels of procollagen III are associated with increased mortality independent of other variables (19, 20, 35). Furthermore, levels of procollagen I correlate with increased risk of dying and are detectable in BALF within 24 h (35). Levels of IL-8/CXCL8 and matrix metalloproteinase-9 correlate with pro-collagen III in pulmonary edema fluid from patients with ARDS (28). These findings suggest that the fibrotic process starts early and is a poor prognostic indicator in ARDS. Furthermore, we have demonstrated evidence of vascular remodeling in ARDS as evidenced by immunolocalization of factor VIII-related Ag, a marker of endothelial cells. This is consistent with our previous findings of neovascularization in IPF and the presence of neovascularization in other chronic inflammatory processes such as psoriasis and rheumatoid arthritis (21, 36, 37, 38, 39).
Our findings of elevated levels of CXC chemokines in BALF are consistent with previous reports of elevated levels of IL-8/CXCL8 in BALF that correlated with progression to ARDS (40, 41). Although undoubtedly neutrophils have an important role in ARDS, acute lung injury can occur in neutropenic patients. There is increasing evidence for alternative biological roles for IL-8/CXCL8 and other ELR+ CXC chemokines in disease processes, specifically in the regulation of angiogenesis (21, 38, 42). Previous workers have demonstrated the presence of angiogenic activity in ARDS (32). Henke et al. (32) demonstrated that BALF from patients with acute lung injury induced endothelial cell migration in vitro and angiogenic activity in vivo (32). They found that that basic fibroblast growth factor accounted for 30% of the angiogenic activity of ARDS BALF. We have shown that the CXC chemokines, IL-8/CXCL8, ENA-78/CXCL5, and IP-10/CXCL10 are important factors that regulate angiogenic activity in IPF (21, 36). We have further extended these studies to the murine model of bleomycin-induced pulmonary fibrosis and have shown that fibrosis can be attenuated either by the inhibition of the angiogenic chemokine macrophage-inflammatory protein 2/CXCL2 or augmentation of the angiostatic chemokine IP-10/CXCL10 (22, 43). These findings are further support for the important role of angiogenesis in the pathogenesis of pulmonary fibrosis related to DAD.
In the present study, we have shown that ELR+ CXC chemokines are a significant source of angiogenic activity in ARDS. Neutralizing Abs to CXCR2 essentially inhibited all of the angiogenic response from ARDS BALF specimens. Furthermore, we found that CXCR2 was significantly expressed on vascular endothelial cells. We also found elevated levels of VEGF in BALF. However, the levels of VEGF were lower than those for the CXC chemokines and we have previously shown that they are equipotent on a nanogram per milliliter basis (44). Furthermore, VEGF did not appear to be a significant contributor to angiogenesis as assessed using the corneal micropocket model. Previous workers have demonstrated elevated levels of VEGF in plasma of patients with ARDS although another group have reported decreased levels in BALF within 7 days of ARDS onset (45, 46). It has been postulated that VEGF contributes to the vascular permeability of ARDS. We cannot exclude a role for VEGF in vascular remodeling in vivo; however, our results would suggest that it plays a minor role. These findings support the presence of a dual regulatory mechanism for net angiogenic activity in ARDS patients, suggesting that ELR+ CXC chemokines are major angiogenic factors in ARDS. In contrast, IP-10/CXCL10, and potentially MIG/CXCL9, are important endogenous angiostatic ELR- CXC chemokines that similar to IPF are expressed at insufficient levels to down-regulate angiogenesis in ARDS.
The predominant cellular sources of the CXC chemokines were mononuclear
cells and in the case of GRO-/CXCL1 mononuclear cells and epithelial
cells. Although there was some overlap in the cellular sources of the
angiogenic chemokines, the fact that GRO-/CXCL1 is also expressed in
epithelial cells indicates a lack of redundancy in chemokine
expression. This is similar to what we have described in IPF specimens
where IL-8/CXCL8 is expressed predominantly by fibroblasts and
ENA-78/CXCL5 is expressed predominantly by epithelial cells, suggesting
that the expression of chemokines with similar biological functions
does not necessarily indicate redundancy of cellular source (21, 36). Furthermore, it indicates a role for nonimmune cells in the
pathogenesis of the fibroproliferation associated with ARDS.
In summary, we have demonstrated that there is increased angiogenic activity in BALF from patients with ARDS that is significantly attributable to CXC chemokines and correlates with the presence of procollagen III and I. This supports the notion that angiogenesis supports fibroproliferation and that ELR+ CXC chemokines have a significant role in the progression of the fibroproliferative phase of ARDS. Furthermore, the receptor responsible for the angiogenic activities of the CXC chemokines is CXCR2, and there is evidence that CXCR2 is down-regulated on neutrophils during sepsis. Therefore, targeting this receptor could potentially inhibit angiogenesis without any detrimental effect on neutrophil function (47). Although one would be reluctant to inhibit potent neutrophil chemoattractants in the setting of infection, selective inhibition of angiogenic chemokines in the lung may have a beneficial role in the prevention of the ongoing fibroproliferative phase of ARDS and deserves further investigation.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael P. Keane, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, Los Angeles, School of Medicine, 900 Veteran Avenue, 14-154 Warren Hall, Los Angeles, CA 90095-1922. E-mail address: mpkeane{at}mednet.ucla.edu
3 Abbreviations used in this paper: DAD, diffuse alveolar damage; ARDS, acute respiratory distress syndrome; VEGF, vascular endothelial growth factor; BALF, bronchoalveolar lavage fluid; ENA-78, epithelial neutrophil-activating protein 78; GRO, growth-related oncogene; IP-10, IFN--inducible protein 10; MIG, monokine induced by IFN-; CXCL, CXC ligand; PIIIP, procollagen III peptide; IPF, idiopathic pulmonary fibrosis.
Received for publication June 3, 2002. Accepted for publication September 18, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC), tumorigenesis and spontaneous metastases. J. Exp. Med. 184:981.-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J. Immunol. 163:5686.This article has been cited by other articles:
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  Y. Zhai, Z. Zhong, C.-Y. A. Chen, Z. Xia, L. Song, M. R. Blackburn, and A.-B. Shyu Coordinated Changes in mRNA Turnover, Translation, and RNA Processing Bodies in Bronchial Epithelial Cells following Inflammatory Stimulation Mol. Cell. Biol., December 15, 2008; 28(24): 7414 - 7426. [Abstract] [Full Text] [PDF]
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 E. C. Keeley, B. Mehrad, and R. M. Strieter Chemokines as Mediators of Neovascularization Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1928 - 1936. [Abstract] [Full Text] [PDF]
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 J. A. Belperio, M. P. Keane, M. D. Burdick, B. N. Gomperts, Y. Y. Xue, K. Hong, J. Mestas, D. Zisman, A. Ardehali, R. Saggar, et al. CXCR2/CXCR2 Ligand Biology during Lung Transplant Ischemia-Reperfusion Injury J. Immunol., November 15, 2005; 175(10): 6931 - 6939. [Abstract] [Full Text] [PDF]
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 M. A. Matthay and G. A. Zimmerman Acute Lung Injury and the Acute Respiratory Distress Syndrome: Four Decades of Inquiry into Pathogenesis and Rational Management Am. J. Respir. Cell Mol. Biol., October 1, 2005; 33(4): 319 - 327. [Full Text] [PDF]
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 Y. Abadie, F. Bregeon, L. Papazian, F. Lange, B. Chailley-Heu, P. Thomas, P. Duvaldestin, S. Adnot, B. Maitre, and C. Delclaux Decreased VEGF concentration in lung tissue and vascular injury during ARDS Eur. Respir. J., January 1, 2005; 25(1): 139 - 146. [Abstract] [Full Text] [PDF]
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G. P. Cosgrove, K. K. Brown, W. P. Schiemann, A. E. Serls, J. E. Parr, M. W. Geraci, M. I. Schwarz, C. D. Cool, and G. S. Worthen Pigment Epithelium-derived Factor in Idiopathic Pulmonary Fibrosis: A Role in Aberrant Angiogenesis Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 242 - 251. [Abstract] [Full Text] [PDF]
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R. D. Sue, J. A. Belperio, M. D. Burdick, L. A. Murray, Y. Y. Xue, M. C. Dy, J. J. Kwon, M. P. Keane, and R. M. Strieter CXCR2 Is Critical to Hyperoxia-Induced Lung Injury J. Immunol., March 15, 2004; 172(6): 3860 - 3868. [Abstract] [Full Text] [PDF]
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 E. Tzima, J. S. Reader, M. Irani-Tehrani, K. L. Ewalt, M. A. Schwartz, and P. Schimmel Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells PNAS, December 9, 2003; 100(25): 14903 - 14907. [Abstract] [Full Text] [PDF]
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