 and
Macrophage Inflammatory Protein-1 Levels in
Bronchoalveolar Lavage Fluid of Patients Affected by
Different Stages of Pulmonary Sarcoidosis
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
ABSTRACT |
|---|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Macrophage inflammatory protein (MIP)-1
and MIP-1
are two
CC chemokines that induce lymphocyte migration. MIP-1 preferentially mediates chemotaxis of CD8 rather than CD4 lymphocytes, whereas the reverse is true for MIP-1. Both these chemokines recognize CCR5 as a cellular receptor in T lymphocytes and
alveolar macrophages. We measured the concentrations of MIP-1
and MIP-1 in bronchoalveolar lavage fluid (BALF) of 30 subjects
affected by different stages of pulmonary sarcoidosis and 18 healthy normal subjects. We also evaluated the expression of
CCR5 in alveolar macrophages and lymphocytes. The BALF concentrations of MIP-1 were significantly increased only in Stage II
and III sarcoidosis. On the contrary, the concentrations of MIP-1
were significantly increased at all stages. A striking increase of
CCR5 expression was observed in both lymphocytes and macrophages of all patients, along with a trend to decreased positivity from Stage I to III of the disease. The MIP-1 concentrations correlated with the number of total (r = 0.65, p = 0.0001) and both
CD4 (r = 0.64, p = 0.0001) and CD8 (r = 0.62, p = 0.0001) lymphocytes; on the contrary, the MIP-1 concentrations correlated only with CD8 lymphocytes (r = 0.45, p = 0.002). Finally, significant negative correlations were observed between the neutrophil
percentage and CCR5 expression in alveolar macrophages (r = 
0.53, p = 0.005) and lymphocytes (r = 0.43, p = 0.01). Our results help to explain the mechanism of CD4 and CD8 recruitment
and the possible involvement of CC chemokines in the fibrotic
progression of sarcoidosis.
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Keywords: macrophage inflammatory protein-1; macrophage inflammatory protein-1; CCR5; bronchoalveolar lavage; sarcoidosis
Sarcoidosis is a systemic granulomatous disease of unknown
cause, that primarily affects the lung and lymphatic system of the
body. Spontaneous remission occurs in nearly two-thirds of patients, but the course is chronic or progressive in 10% to 30% (1). The early sarcoid reaction is characterized by the accumulation of activated T cells and macrophages at sites of ongoing inflammation, notably in the lung (2). In most patients, sarcoid T
lymphocytes belong to the helper CD4 phenotype; rarely are the
accumulating cells predominantly CD8+ lymphocytes (3).
These cells spontaneously release interferon-
(IFN-) and interleukin-2 (IL-2), cytokines associated with a T helper cell, type
1 (Th1) T-cell response (4, 5). One key cytokine for the induction of Th1 cells is IL-12, a product of activated macrophages
and a stronger inducer of Th1 responses. Increased concentrations of IL-12 upregulate the development of Th1 cells and amplify the release of Th1 cytokines, especially IFN- (6). Sarcoid
alveolar macrophages behave as versatile secretory cells that release other cytokines such as tumor necrosis factor- (TNF-),
IL-15, growth factor, and chemokines such as monocyte chemotactic protein-1 (MCP-1), RANTES (regulated upon activation,
normal T-cell expressed and secreted), and macrophage inflammatory proteins 1 (MIP-1) and 1 (MIP-1). (7, 8).
In sarcoidosis, these chemokines have been found in bronchoalveolar lavage fluid (BALF) and cell culture supernatants; they mediate the major part of monocyte, lymphocyte, and neutrophil chemotactic activity and are capable of activating these cells (8). In line with this notion is the observation of elevated chemokine release in patients with active or progressive disease. In human and animal models of idiopathic pulmonary fibrosis, a critical role of chemokines in the initiation and maintenance of pulmonary lesions and their angiogenesis has been established (9). Studies on pulmonary fibrosis presenting in the course of sarcoidosis are still lacking (8).
The balance between two macrophage-derived CC chemokines, MIP-1 and MIP-1, could potentially be involved in
sustaining inflammation and a chronic course in sarcoidosis
because the first preferentially mediates chemotaxis of CD8
rather than CD4 lymphocytes, whereas the reverse is true for
MIP-1 (10). Both these chemokines recognize CCR5 as a cellular receptor in activated T lymphocytes and alveolar macrophages (11). Chemokine receptor expression could constitute a major regulatory element for the composition of the lymphocytic infiltrates in different patterns of inflammatory pathology. CCR5 is expressed at high levels in CD4+ Th1 lymphocytes, and its stimulation induces an intracellular biochemical
cascade with an increased production and release of IL-2 and
IFN- (12). To evaluate the role of MIP-1, MIP-1, and their
receptor CCR5 in the pathogenesis and progression of sarcoidosis, we evaluated the chemokine concentrations in BALF
and receptor expression in alveolar cells of patients affected
by different stages of this granulomatous disease.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Study Population
Forty-eight nonsmokers were included in the study: 18 healthy control subjects and 30 patients affected by pulmonary sarcoidosis diagnosed with clinical, functional, radiographic, and histologic criteria. None of the patients had evidence of an alternative diagnosis or exposure to any inorganic material known to cause granulomatous disease. Informed consent was obtained from each subject, and the protocol was approved by the review board of the Scientific Institute in Veruno, Italy.
The 30 patients affected by sarcoidosis were divided into three groups on the basis of chest roentgenogram (13): 12 with Stage I sarcoidosis (bilateral hilar lymphadenopathy without parenchymal involvement), 9 with Stage II (bilateral hilar lymphadenopathy with parenchymal involvement) and 9 with Stage III/IV (pulmonary infiltrates or end-stage pulmonary fibrosis without hilar lymphadenopathy). Table 1 shows subjects' demographic and functional data. Treatment with steroid or nonsteroid antiinflammatory drugs was stopped at least 1 mo before inclusion. None of the subjects had ever been prescribed cytotoxic drug therapy before inclusion.
|
Pulmonary Function Tests
Pulmonary function testing included the measurement of forced expiratory volume in one second (FEV1), forced vital capacity (FVC) (6200 Autobox Pulmonary Function Laboratory; Sensormedics Corp., Yorba Linda, CA), and diffusing capacity for carbon monoxide (DLCO), determined by the single-breath method (2200 Pulmonary Function Laboratory; Sensormedics).
Processing of BAL
BAL was performed as previously described (14). Cytocentrifuge
(Cytospin II; Shandon, London, UK) slides, prepared with native
fluid, were stained with May-Grunwald Giemsa to determine the cell
differentials, and those used for immunocytochemistry were fixed for
2 min with acetone and frozen at 80°C until analysis. BAL supernatants were immediately stored at 80°C until analysis.
Immunocytochemistry
The expression of CD4, CD8, and CCR5 in BAL cells was assessed by immunocytochemistry on frozen cytocentrifuge slides. The anti-CD4 antigen (M834) and anti-CD8 antigen (M7052) were purchased from Dako (Copenhagen, Denmark); the anti-CCR5 (MAB 181) was purchased from R & D Systems (Abington, UK). Monoclonal antibody binding was detected with the alkaline phosphatase anti-alkaline phosphatase method (Dako APAAP kit system K670) and fast-red substrate.
Immunoassay
The levels of the chemokines in BALF, concentrated at least 10-fold
with Centricon-3 concentrators (Amicon Inc., Beverly, MA), were obtained with Quantikine MIP-1, MIP-1 ELISA kits purchased from
R & D Systems (Abington, UK). This assay employs the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for the chemokine is precoated onto a microtiter plate. The kits contain respectively Escherichia coli-expressed recombinant human MIP-1, recombinant human MIP-1 (Act-2 variant, expressed in Sf
21 insect cells using a baculovirus expression system), and antibodies
raised against recombinant human MIP-1 and MIP-1. The standard
curves were prepared from 0 pg/ml to 1,000 pg/ml. The lower limits of
detection of the kits (supplier's data) were as follows: MIP-1 6.0 pg/ml;
MIP-1 4.0 pg/ml. Standards and samples were run in duplicate.
Statistical Analysis
Demographic and functional data are reported as mean and standard deviation; the other results are expressed as median (range). Differences between the four groups were assessed with analysis of variance (ANOVA), Student's t test, Kruskal-Wallis, and Mann-Whitney U tests. Spearman's rank correlation coefficient was used to study correlations between chemokine concentrations and both pulmonary function tests and BAL cellular populations. Analysis was performed with a personal computer (Vectra.VE17.C500; Hewlett Packard, Grenoble, France) and Statview + Graphics software (Abacus Concepts, Inc., Berkeley, CA). Statistical significance was defined as p < 0.05.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Functional Data
Table 1 shows the demographic and functional data of the study population. In accord with the evolution of the disease, we observed a progressive functional impairment with a decrease of DLCO and PaO2 from Stage I (98.0 ± 8.9% and 85.4 ± 3.8 mm Hg) to Stage III of sarcoidosis (53.8 ± 14.4% and 72.3 ± 18.2 mm Hg).
Differential Cell Counts of BALF and Lymphocyte Subsets
The BAL differential cell populations, shown in Table 2, besides the well-known increase of cellularity with lymphocytosis, reflect the fibrotic evolution of sarcoidosis with a significant progressive increase of neutrophils [from 2.6 (0.7 to 12.7) to 11.6 (1.9 to 103.0) × 103/ml, p < 0.01] and eosinophils [from 0.9 (0 to 2.8) to 5.5 (0.4 to 15.6) × 103/ml, p < 0.005] from Stage I to III.
|
The increase of CD4+ T lymphocytes in all the groups of patients affected by sarcoidosis compared with control subjects is evident in Table 3, expressed as a percentage. Interestingly, between the sarcoidosis groups, we observed a decrease of CD4+ (68.4 [54.2 to 87.8] versus 45.5 [20.2 to 64.0] %, p < 0.01) and an increase of CD8+ lymphocytes (14.3 [6.1 to 45.0] versus 41.0 [29.4 to 48.6] %, p < 0.01) in Stage III compared with Stage I, and consequently a decrease of CD4/CD8 ratio (4.9 [1.9 to 10.3] versus 1.2 [0.5 to 1.7], p < 0.001). The same result was observed analyzing the absolute number of CD4+ and CD8+ lymphocytes per milliliter (data not shown).
|
BALF Levels of MIP-1 and MIP-1
The increase of MIP-1 (Figure 1) was statistically significant
compared with control subjects (1.2 [0 to 3.8] pg/ml) only for
Stage II (2.2 [1.0 to 4.3] pg/ml, p < 0.02) and Stage III (2.5 [1.6 to 13.1] pg/ml, p < 0.001) sarcoidosis groups; no significant differences were observed with Stage I (1.6 [0 to 3.8] pg/ml p = not significant [NS]).
|
The concentrations of MIP-1, as shown in Figure 1, were
higher in BALF at Stage I (8.8 [1.2 to 68.2] pg/ml), Stage II
(14.8 [8.6 to 41.8] pg/ml), and Stage III (9.6 [1.6 to 14.6] pg/ml) sarcoidosis than in the control group (3.4 [0.3 to 6.8] pg/ml).
Relationship between BAL Characteristics and Concentrations
of MIP-1 and MIP-1
The concentrations of both MIP-1 (r = 0.65, p = 0.0001) and
MIP-1 (r = 0.4, p = 0.007) were correlated with total number of lymphocytes. Including all subjects in the statistical analysis, a positive correlation (Figure 2) was found between the
BALF levels of MIP-1 and both CD4+ (r = 0.64, p = 0.0001)
and CD8+ (r = 0.62, p = 0.0001), whereas the concentrations
of MIP-1 were correlated only with CD8 lymphocytes (r = 0.45, p = 0.002). These correlations were not statistically significant if we discarded the control subjects from the analysis.
Moreover MIP-1 concentrations significantly correlated with
the number of neutrophils (r = 0.46, p = 0.002).
|
CCR5-positive Cells in BALF
Figure 3 shows a significant difference at the immunocytochemistry reaction of BALF cells with anti-CCR5 antibody between a patient affected by sarcoidosis and a control individual. Both macrophages and lymphocytes were CCR5+ in BAL of patients with sarcoidosis; on the contrary, most of the cells were negative in control subjects. In fact, levels of CCR5 expression in lymphocytes and macrophages of sarcoidosis patients were almost always above the upper limit of variation range of normal subjects (Figure 4 and Table 3). Moreover we observed a significant decrease both in absolute values (data not shown) and in percentage (p < 0.001) of CCR5+ lymphocytes and macrophages from Stage I to Stage III of the sarcoidosis groups (Figure 4 and Table 3).
|
|
Evaluating only patients affected by sarcoidosis, a negative
correlation (Figure 5) was observed comparing the percentage of neutrophils with the percentage of CCR5+ lymphocytes (r = 0.43, p < 0.01) and with the percentage of CCR5+ alveolar
macrophages (r = 0.53, p < 0.005).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Our findings demonstrate an elevated level of two CC chemokines, MIP-1 and MIP-1, in BALF from patients affected
by different stages of sarcoidosis. These results were associated with an increased expression of CCR5, the specific receptor for the two chemokines, in lymphocytes and alveolar macrophages.
Most studies on sarcoidosis have been conducted on the
first stage of the disease with the evidence of an immunologic
Th1 type T-cell response (1). No studies have shown why the
lung involvement persists in some patients but not in others,
and no studies have shown how persistent disease results in
lung injury and fibrosis (1). Stages II and III, compared with
Stage I, are characterized by modifications of cellular populations in the lung with a progressive increase of neutrophils and
eosinophils associated with the deterioration of clinical and
functional parameters. Also, the progressive decrease of CD4/
CD8 ratio from the first to the third stage of sarcoidosis is in
agreement with previous studies (15, 16). Prasse and coworkers recently observed that CD8 T lymphocytes have the potential to produce IL-2, TNF-, and INF- in a similar fashion
to CD4+ cells; hence CD8 could be a relevant source of these
proinflammatory cytokines in patients with Stage II and III
sarcoidosis (17). Studies concerning an involvement of T cells
in pulmonary fibrosis studied in animals with bleomycin-induced
fibrosis model are contradictory (9, 18).
The synthesis of CC chemokines MIP-1, MIP-1, and the
expression of their receptor CCR5 are associated with a type 1 immune response (12, 19). In our study, the MIP-1 concentrations were significantly increased only in the BALF of patients
affected by Stage II and III sarcoidosis (Figure 1) where an involvement of pulmonary interstitium was evident. An important role of MIP-1 has been observed in the inflammatory
process of fibrotic lung diseases and in the bleomycin-induced
model of pulmonary fibrosis in mice (9, 20), in which treatment with anti-MIP-1 antibody reduced the net lung hydroxyproline content by 49% compared with bleomycin-challenged mice treated with nonimmune serum (21). McKee and
coworkers have observed that hyaluronan fragments generated under inflammatory conditions induce an influx of inflammatory cells, deposition of collagen, and also the expression of several macrophage genes, including the chemokine
gene family for MIP-1 and MIP-1. (22). We observed significant correlations of MIP-1 concentrations in BALF with
both CD8 lymphocytes and neutrophils, in agreement with
previous observations of a nonselective chemotactic activity of
this chemokine (9) and with Cocchi and coworkers who documented the ability of CD8+ lymphocytes to produce MIP-1, MIP-1, and RANTES (23).
Finally, our study reports a significant negative correlation
between MIP-1 concentrations and PaO2 (r = 0.43, p = 0.01) and DLCO (r = 0.58, p = 0.001), both indicating functional deterioration of pulmonary exchange induced by fibrotic evolution. Our results and data from the literature lead
one to speculate a direct involvement of MIP-1 in the inflammatory process underlying the fibrotic stage of sarcoidosis.
Few studies have examined the role of MIP-1 in pulmonary disease, and to our knowledge this is the first investigation evaluating its involvement in the fibrotic progression that
may occur in sarcoidosis. In a recent study, Katoh and coworkers evaluated MIP-1 BALF concentrations in patients affected by Stage I sarcoidosis, idiopathic pulmonary fibrosis,
and eosinophilic pneumonia (24); MIP-1 concentrations were
higher only in BALF of patients affected by eosinophilic pneumonia and correlated with the number of eosinophils but not
with other cell populations. In our study, we observed an increase of MIP-1 across all sarcoidosis groups (Figure 1) with
a good correlation with CD4+ (Figure 4) and CD8+ lymphocytes, in agreement with the observation that this chemokine
is produced by T cells and involved in their chemotaxis (10,
23). No correlations were found between MIP-1 concentrations in BALF of sarcoidosis and the common cellular markers of fibrotic stage such as neutrophils and eosinophils or
functional data. The differences between our results and those
of Katoh and coworkers could be explained by the different
methodologies in the treatment of BALF (we concentrated the supernatants) and number of patients studied, which was
far higher in our study. Interestingly, Bless and coworkers recently observed in rats an important role played by MIP-1 in
IgG immune complex-induced acute lung injury, in which it
operates as an autocrine activator of alveolar macrophages
and directly causes an increase of lung vascular permeability
(25). In the pathogenetic mechanism of sarcoidosis some aspects are very similar, with an involvement of alveolar macrophages and alteration of vascular permeability (8). According
to our findings, MIP-1 appears to be involved from the earliest phases of the disease. On the contrary, MIP-1 seems to
participate prevalently in the advanced stages of sarcoidosis.
Both MIP-1 and MIP-1 recognize CCR5 as a cellular receptor (11), which, as observed by Loetscher and coworkers, is
characteristic of Th1 inflammatory response. CCR5 stimulation induces an increased production of IL-2 and IFN- (12),
in agreement with the increase of these two cytokines observed in sarcoidosis and involved in the granulomatous response
(1, 8). Interestingly, we noted a progressive decrease in CCR5
expression in both BAL macrophages and lymphocytes of patients with Stage II and III sarcoidosis. This downregulation of
CCR5 expression could be related with the fibrotic stages of
the disease. Petrek and coworkers recently observed in Czech
patients with pulmonary sarcoidosis without spontaneous resolution and requiring corticosteroid therapy an increase of
CCR5 
32 allelic frequency (26) and a 32-bp deletion in the
CCR5 gene (CCR5 32) resulting in a nonfunctional surface receptor molecule, unable to bind its chemokine ligand RANTES, MIP-1, and MIP-1 (27). We did not study these genetic characteristics, but parallel to a decrease in efficiency there could also be
a reduction in the receptor expression associated with disease
progression. Moreover, because CCR5 expression is a characteristic of the Th1 immune reaction (12), its downregulation
observed in advanced stages of the disease could be evidence
of a switch to Th2 type T cells that may occur in patients with
sarcoidosis evolving toward lung fibrosis, as demonstrated by
Kunkel and coworkers (28). We also showed a statistically significant negative correlation between CCR5 expression and
neutrophils (Figure 5), inflammatory cells involved in the fibrotic progression; in our previous study on CCR5 expression
in alveolar macrophages and lymphocytes of patients affected
by chronic bronchitis, we found a similar result (29). In an in
vitro study, neutrophils with their products were able to inhibit some lymphocyte antigen expression such as CD3, CD4,
CD8, and CD2 (30). Therefore, even if it is still not documented,
we can speculate a similar activity of downregulation played by
neutrophils on the CCR5 expression.
In conclusion, all of our observations in this study point to
an important role played by two CC chemokines, MIP-1 and
MIP-1, and their receptor CCR5 in the pathogenesis of the
inflammatory process in both the earlier and fibrotic stages of
pulmonary sarcoidosis. Because markers for progression to fibrosis are lacking, further studies on cytokines and chemokines involving populations at different stages of the disease
and, possibly, longitudinal studies may help to clarify why some
patients recover spontaneously and others develop pulmonary fibrosis.
| |
Footnotes |
|---|
Correspondence and requests for reprints should be addressed to Dr. Armando Capelli, Divisione di Pneumologia, Centro Medico di Riabilitazione, Veruno (Novara), Italy. E-mail: acapelli{at}fsm.it
(Received in original form June 20, 2001 and accepted in revised form October 17, 2001).
Acknowledgments: The authors thank Rosemary Allpress for editorial assistance.
Supported in part by a "Ricerca Corrente" grant from the Ministry of Health, Rome, Italy.
| |
References |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1. American Thoracic Society. Statement on Sarcoidosis. Am J Respir Crit Care Med 1999;160:736-755.
2. Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981; 305: 429-434 [Abstract].
3. Agostini C, Trentin L, Zambello R, Bulian P, Siviero F, Masciarelli M, Festi G, Cipriani A, Semenzato G. CD8 alveolitis in sarcoidosis: incidence, phenotypic characteristics, and clinical features. Am J Med 1993; 95: 466-472 [Medline].
4. Konishi K, Moller DR, Saltini C, Kirby M, Crystal RG. Spontaneous expression of the interleukin 2 receptor gene and presence of functional interleukin 2 receptors on T lymphocytes in the blood of individuals with active pulmonary sarcoidosis. J Clin Invest 1988; 82: 775-781 .
5. Robinson RBW, McLemore TL, Crystal RG. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest 1988; 75: 1488-1505 .
6. Moller DR, Forman JD, Liu MC, Noble PW, Greenlee BM, Vyas P, Holden DA, Forrester JM, Lazarus A, Wysocka M, Trinchieri G, Karp C. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156: 4952-4960 [Abstract].
7. Agostini C, Trentin L, Facco M, Sancetta R, Cerutti A, Tassinari C, Cimarosto L, Adami F, Cipriani A, Zambello R, Semenzato G. Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J Immunol 1996; 157: 910-918 [Abstract].
8. Müller-Quernheim J. Sarcoidosis: immunopathogenetic concepts and their clinical application. Eur Respir J 1998; 12: 716-738 [Abstract].
9. Smith RE, Strieter RM, Phan SH, Kunkel SL. C-C chemokine: novel mediators of the profibrotic inflammatory response to bleomycin challenge. Am J Respir Cell Mol Biol 1996; 15: 693-702 [Medline].
10.
Taub DD,
Conlon K,
Lioyd AR,
Oppenheim JJ,
Kelvin DJ.
Preferential
migration of activated CD4+ and CD8+ T cells in response to MIP-1
alpha and MIP-1 beta.
Science
1993;
260:
355-358
11.
Wu L,
La Rosa G,
Kassam N,
Gordon CJ,
Heath H,
Ruffing N,
Chen H,
Humblias J,
Samson M,
Parmentier M,
Moore JP,
Mackay CR.
Interaction of chemokine receptor CCR5 with its ligands: multiple domains
for HIV-1 gp 120 binding and a single domain for chemokine binding.
J Exp Med
1997;
186:
1373-1381
12. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature 1998; 391: 344-345 [Medline].
13.
DeRemee RA.
The roentgenographic staging of sarcoidosis.
Chest
1983;
83:
128-133
14. Capelli A, Lusuardi M, Carli S, Donner CF. Acid phosphatase (E.C. 3.1.3.2.) activity in alveolar macrophages from patients with active sarcoidosis. Chest 1991; 99: 545-550 .
15. Greening AP, Nunn P, Dobson N, Rudolf M, Rees AD. Pulmonary sarcoidosis: alteration in bronchoalveolar lymphocytes and T cell subsets. Thorax 1985; 40: 278-283 [Abstract].
16. Ward K, O'Connor C, Odlum C, Fitzgerald MX. Prognostic value of bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation. Thorax 1989; 44: 6-12 [Abstract].
17. Prasse A, Georges CG, Biller H, Hamm H, Matthys H, Luttmann W, Virchow JC Jr. . Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. Clin Exp Immunol 2000; 122: 241-248 [Medline].
18. Helen M, Lake-Bullock V, Zhu J, Hao H, Cohen DA, Kaplan AM. T cell independence of bleomycin-induced pulmonary fibrosis. J Leukoc Biol 1999; 65: 187-195 [Abstract].
19. Schrum S, Probst P, Fleischer B, Zipfel PF. Synthesis of the CC-chemokines MIP-1alpha, MIP-1beta, and RANTES is associated with the type 1 immune response. J Immunol 1996; 157: 3598-3604 [Abstract].
20. Ziegenhagen MW, Schrum S, Zissel G, Zipfel PF, Schlaak M, Muller-Quernheim J. Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. J Investig Med 1998; 46: 223-231 [Medline].
21.
Smith RE,
Strieter RM,
Phan SH,
Lukacs NW,
Huffnagle GB,
Wilke CA,
Burdick MD,
Lincoln P,
Evanoff H,
Kunkel SL.
Production and
function of murine macrophage inflammatory protein-1 bleomycin-induced lung injury.
J Immunol
1994;
153:
4704-4712
[Abstract].
22. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, Noble PW. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. J Clin Invest 1996; 98: 2403-2413 [Medline].
23.
Cocchi F,
DeVico AL,
Garzino-Demo A,
Arya SK,
Gallo RC,
Lusso P.
Identification of RANTES, MIP-1, and MIP-1 as the major HIV-suppressive factors produced by CD8+ T cell.
Science
1995;
270:
1811-1815
24. Katoh S, Matsumoto N, Fukushima K, Mukae H, Kadota J, Kohno S, Matsukura S. Elevated chemokine levels in bronchoalveolar lavage fluid of patients with eosinophilic pneumonia. J Allergy Clin Immunol 2000; 106: 730-736 [Medline].
25.
Bless NM,
Huber-Lang M,
Guo R,
Warner RL,
Schmal H,
Czermak BJ,
Shanley TP,
Crouch D,
Lentsch AB,
Sarma V,
Mulligan MS,
Friedl HP,
Ward PA.
Role of CC chemokines (macrophages inflammatory
protein-1, monocyte chemoattractant protein-1, RANTES) in acute
lung injury in rats.
J Immunol
2000;
164:
2650-2659
26.
Petrek M,
Drabek J,
Kolek V,
Zlamal J,
Welsh KI,
Bunce M,
Weigl E,
du Bois RM.
CC Chemokine receptor gene polymorphisms in Czech
patients with pulmonary sarcoidosis.
Am J Respir Crit Care Med
2000;
162:
1000-1003
27. Mantovani A. The chemokine system: redundancy for robust outputs. Immunol Today 1999; 20: 254-257 [Medline].
28. Kunkel SL, Lucaks NW, Strieter RM, Chensue SW. Th1 and Th2 responses regulate experimental lung granuloma development. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 120-128 . [Medline]
29. Capelli A, Di Stefano A, Gnemmi I, Lusuardi M, Balbo P, Balbi B, Donner CF. Downregulation of CCR5 receptor expression in lymphocytes and alveolar macrophages of smokers with chronic obstructive pulmonary disease (COPD). Eur Respir J 2000;16(Suppl. 31):214s.
30. Doring G, Frank F, Boudier C, Herbert S, Fleischer B, Bellon G. Cleavage of lymphocyte surface antigens CD2, CD4, CD8 by polymorphonuclear leukocyte elastase and cathepsin G in patients with cystic fibrosis. J Immunol 1995; 154: 4842-4850 [Abstract].
This article has been cited by other articles:
 |
|
 |
|
  I. G. Luzina, N. W. Todd, A. T. Iacono, and S. P. Atamas Roles of T lymphocytes in pulmonary fibrosis J. Leukoc. Biol., February 1, 2008; 83(2): 237 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kriegova, C. Melle, V. Kolek, B. Hutyrova, F. Mrazek, A. Bleul, R. M. du Bois, F. von Eggeling, and M. Petrek Protein Profiles of Bronchoalveolar Lavage Fluid from Patients with Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., May 15, 2006; 173(10): 1145 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Takeuchi, K. Oh-i, J. Suzuki, T. Hattori, A. Takeuchi, Y. Okunuki, Y. Usui, and M. Usui Elevated Serum Levels of CXCL9/Monokine Induced by Interferon-{gamma} and CXCL10/Interferon-{gamma}-Inducible Protein-10 in Ocular Sarcoidosis. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1063 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Spagnolo, E. A. Renzoni, A. U. Wells, S. J. Copley, S. R. Desai, H. Sato, J. C. Grutters, A. Abdallah, A. Taegtmeyer, R. M. du Bois, et al. C-C Chemokine Receptor 5 Gene Variants in Relation to Lung Disease in Sarcoidosis Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 721 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Capelli, A. Di Stefano, I. Gnemmi, and C. F. Donner CCR5 expression and CC chemokine levels in idiopathic pulmonary fibrosis Eur. Respir. J., April 1, 2005; 25(4): 701 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Thomas and G. W. Hunninghake Sarcoidosis JAMA, June 25, 2003; 289(24): 3300 - 3303. [Full Text] [PDF]
|
|
|
|
|
|
A. Gibejova, F. Mrazek, D. Subrtova, V. Sekerova, J. Szotkowska, V. Kolek, R. M. du Bois, and M. Petrek Expression of Macrophage Inflammatory Protein-3{beta}/CCL19 in Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1695 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fehrenbach, G. Zissel, T. Goldmann, T. Tschernig, E. Vollmer, R. Pabst, and J. Muller-Quernheim Alveolar macrophages are the main source for tumour necrosis factor-{alpha} in patients with sarcoidosis Eur. Respir. J., March 1, 2003; 21(3): 421 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Tobin Tuberculosis, Lung Infections, Interstitial Lung Disease, and Journalology in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 345 - 355. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Cell Mol. Biol. |