close

Вход

Забыли?

вход по аккаунту

?

Interstitial lung disease in scleroderma analysis by bronchoalveolar lavage.

код для вставкиСкачать
1254
INTERSTITIAL LUNG DISEASE IN SCLERODERMA
Analysis by Bronchoalveolar Lavage
RICHARD M. SILVER, JOHN F. METCALF, JOHN H. STANLEY, and E. CARWILE LEROY
Interstitial pulmonary fibrosis is a common feature of scleroderma (systemic sclerosis) which may
result in impairment of pulmonary function and may be
a major determinant of morbidity and mortality. Clinicopathologic observations suggest that interstitial and
alveolar inflammation may appear prior to fibrosis.
Using the bronchoalveolar lavage (BAL) technique, we
have characterized the nature of the inflammatory
process in the lower respiratory tracts of 19 nonsmoking scleroderma patients. Eleven of 19 patients
(58 96) had increased percentages of neutrophils andor
eosinophils in BAL fluid. Five of 10 patients (50%) had
elevations of IgG in BAL fluid. The presence of neutrophils was associated with a decreased lung diffusing
capacity for carbon monoxide (P< 0.05) and with more
advanced radiographic features of interstitial fibrosis in
patients with disease of more than 1 year’s duration.
This study suggests that scleroderma lung involvement
may be characterized by an inflammatory alveolitis and
that the presence of such inflammation may relate to the
severity of the pulmonary disease.
Fibrosis of the pulmonary parenchyma is a
well-defined feature of scleroderma (systemic sclero_____
From the Division of Rheumatology and Immunology and
the Division of Pulmonary Medicine, Department of Medicine, and
the Department of Radiology, Medical University of South Carolina, Charleston.
Supported in part by the National Institutes of Health
(grants RR1070 and AM-30431), the RGK Foundation, and the
United Scleroderma Foundation.
Richard M. Silver, MD; John F. Metcalf, MD; John H.
Stanley, MD; E. Carwile LeRoy, MD.
Address reprint requests to Richard M. Silver, MD, Division of Rheumatology and Immunology, Room 912, Clinical Sciences Building, 171 Ashley Avenue, Charleston, SC 29425.
Submitted for publication January 24, 1984; accepted in
revised form June 12, 1984.
Arthritis and Rheumatism, Vol. 27, No. 11 (November 1984)
sis), which results in significant impairment of lung
function. Many studies have dealt with alterations of
pulmonary function in scleroderma patients, which are
the result of interstitial pulmonary inflammation a n d
or fibrosis with associated ventilation-perfusion abnormalities (1-7). Postmortem studies have confirmed
the frequent presence of interstitial fibrosis (2,8).
Studies correlating pulmonary functional abnormalities with histopathology have demonstrated interstitial
and alveolar inflammation prior to the appearance of
fibrosis (9). Few studies have attempted to characterize this inflammatory process, and those few are
difficult to interpret due to the small numbers of
patients studied and the inclusion of smokers (10-12).
We have used bronchoalveolar lavage (BAL) to
sample the fluid lining the epithelial surface of the
lower respiratory tracts of scleroderma patients and
have characterized certain cellular and protein constituents of such fluid. In this report, we describe the
results of such studies in 19 nonsmoking scleroderma
patients. Our data suggest that a significant percentage
of scleroderma patients have an active alveolitis. We
propose that the presence of inflammatory cells in
scleroderma bronchoalveolar lavage fluid may represent a potentially reversible component of pulmonary
scleroderma.
PATIENTS AND METHODS
Patients. Twenty-one patients with scleroderma (systemic sclerosis) were entered into a study of pulmonary
involvement and its assessment by bronchoalveolar lavage.
Patients fulfilling the American Rheumatism Association
(ARA) preliminary criteria for the classification of systemic
sclerosis (13), with or without clinical evidence of pulmonary
involvement, were randomly selected for study. Patients
with a recent history of cigarette smoking, with lower
LUNG DISEASE IN SCLERODERMA
1255
respiratory tract infection, or with a history of chronic
bronchitis were excluded from the study. Patients were
admitted to the General Clinical Research Center of the
Medical University of South Carolina, where clinical evaluation, chest radiographs, and pulmonary function tcsts were
performed. The clinical features of the study population are
presented in Table 1. Disease duration was defined as the
time from clinical diagnosis to study entry. Raynaud’s
phenomenon and scleroderma skin changes were defined as
previously outlined by the ARA Scleroderma Criteria Cooperative Study (13). The following criteria were used to define
extrapulmonary visceral involvement: 1) esophageal-hypoperistalsis or aperistalsis of the distal esophagus demonstrated by esophageal manometry or by cineesophagram; 2)
muscle-proximal muscle weakness and I or more of the
following: (a) elevated creatine phosphokinase or aldolase
levels; (b) abnormal electromyographic findings suggestive
of inflammatory myopathy ; or (c) inflammatory cell infiltration of muscle shown on biopsy; 3) renal-rapid, progressive
renal failure, creatinine clearance < 15 ml/minute, proteinuria >2 g d 2 4 hours, or persistent cellular casts in the urine
sediment; 4) cardiovascular-clinical1 y evident cardiomyopathy, pericarditis, or ventricular arrhythmia on a 12-lead
electrocardiogram or Holter monitor, or abnormal echocardiogram consisting of left ventricular wall thickening in the
absence of hypertension or right ventricular dilatation.
Antinuclear antibodies were determined in the hospital laboratory, using rat liver and HEp-2 cell substrates.
Nailfold capillary microscopy was performed by Dr. H. R.
Maricq, as previously described (14). Standard high kilovoltage posteroanterior and lateral chest radiographs were obtained prior to pulmonary lavage. The films were evaluated
by a radiologist who was unaware of the clinical data. The
radiographic findings were categorized as abnormal if reticulo-nodular densities consistent with interstitial lung disease were present. Radiographic abnormalities were further
delineated according to location. Lung tissue was obtained
from 2 patients; in addition to trichrome and hematoxylin
and eosin stains, alveolar and interstitial neutrophils were
identified in tissue sections by a neutrophil-specific esterase
stain (15).
Tests of pulmonary function. Standard spirometric
measurements of lung volume, flow indices, and diffusing
capacity were performed on each patient. Lung volumes
consisting of vital capacity, residual volume, and total lung
capacity were measured in the sitting position on a computerized lung analyzer (Collins Computerized Modular Lung
Analyzer, Braintree, MA). Total lung volume was measured
by the helium dilution technique and by body plethysmography (Collins Body Plethysmograph). Airway disease was
evaluated with the I-second forced expiratory volume/
forced vital capacity ratio (FEVJFVC). The best FEV, and
FVC obtained in 3 efforts were used (16). The maximum
expiratory flow rate at 50% and 75% vital capacity with air
and 80% helium-20% O2 was measured (17). The diffusing
capacity of the lung was measured as the single breath
diffusing capacity (DLco). The degree of impairment was
considered mild if the percent predicted was 65-80%, mod-
Table 1. Clinical characteristics of scleroderma patients studied by bronchoalveolar lavage*
Extrapulmonary organ involvement
Patient
Agelsex
Group I+
1
2
3
4
5
6
7
8
9
10
II
11/19
0(58%)
Group II$
12
13
14
15
16
17
18
19
8/19
R(42%)
I
52lF
21lM
36lF
30lM
321F
48lM
23lF
441M
58lM
30lF
32lF
36.9 t 3.6
F:M = 1.2
48lF
49lM
35lM
431F
40lM
64lM
42lF
37lM
44.7 2 3.2
F:M = 0.4
Disease
duration
(years)
5
I1
I
4
1
3
3
15
5
7
2
Sclerodactyly
Trunk
Esophagus
+
+
+
+
+
t
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
t
1
5.1
Skin
RP
1.3
2.8
2
+
I1
=
ANA
+
+
+
+
+
+
ND
ND
i
+
+
ND
ND
A
+
+
t
1111 1
(100%)
611 I
(54%)
1111I
(100%)
8110
(80%)
(1008)
-
+
-
+
f
+
+
+
+
+
+
+
818
( 100%)
718
(87%)
11111
+
+
+
+
t
+
+
i
-
+
+
+
+
+
418
(50%)
t
t
+
f
+
318
(37%)
(12%)
(12%)
* RP = Raynaud’s phenomenon; ANA = antinuclear antibodies; + = positive; - = negative: ND
t Group I = patients with abnormal cellular content of bronchoalveolar lavage fluid.
$ Group
Muscle
+
+
+
0.5
-
+
Renal
+
+
+
+
+
(100%)
4
5
1
2
I
2
4
3
t
Cardiac
Sclerodermatype
capillary
morphology
patients with normal cellular content of bronchoalveolar lavage fluid.
=
(25%)
not done.
+
+
+
f
818
+
+
ND
+
+
+
ND
717
(100%)
417
(57%)
-
+
+
+
SILVER ET AL
1256
erate 50-65%, severe 35-50%, and very severe <35% (these
figures are adjusted upward 10% for black patients) (16).
Bronchoscopy and bronchoalveolar lavage. Bronchoscopy was done with the approval of the Human Research
Committee at the Medical University of South Carolina.
Informed consent was obtained from all patients. Bronchoalveolar lavage was performed as previously described
(18,19). Briefly, local anesthesia in the upper respiratory
tract was obtained with topical lidocaine spray (2%), after
which a fiberoptic bronchoscope (Olympus Corp. of America, New Hyde Park, NY) was wedged in a subsegment of the
right middle lobe. Lavage was performed by instillation and
immediate withdrawal by syringe of 5 60-ml boluses of sterile
0.9% sodium chloride solution, all at one site. The recovered
lavage fluid was pooled and filtered through a double layer of
sterile gauze to remove mucus, after which it was added to
an equal volume of Hanks’ balanced salt solution (HBSS;
Gibco, Grand Island, NY) and maintained at 4°C. The fluid
was then centrifuged at 5OOg for 15 minutes at room temperature, and the cell-free supernatant fluid immediately frozen
at -20°C for future analysis.
Cellular analysis. The cell pellet was resuspended in
HBSS and the cell number counted in a modified Neubauer
hemocytometer. Air-dried cytocentrifuge smears stained
with Wright’s stain and with a nonspecific esterase stain for
the identification of monocytes and macrophages (20) were
prepared. Slides were examined by light microscopy and 400
or more cells from each sample were scored as alveolar
macrophages, lymphocytes, neutrophils, or eosinophils. Patients were divided into 2 groups, normal and abnormal, on
the basis of the lavage cell differential. Normal values were
established from lavage fluid samples of 7 nonsmoking
normal control subjects and consisted of 95.1 2 4.3% (mean
k SD) alveolar macrophages, 0.6 ? 0.8% neutrophils, 3.6 k
3.0% lymphocytes, and 0.7 2 1.5% eosinophils. These
values are consistent with those of nonsmoking control
subjects studied by other investigators (12,21,22).Abnormal
values were defined as greater than 2 standard deviations
above the mean of normal control subjects.
Protein analysis. The cell-free supernate was thawed
and concentrated to a final volume of 1.0 ml using vacuum
filtration with a molecular filtration membrane (Immersible
Cx-10 Filter Units, 10,000 nmwl, Millipore Corp., Bedford,
MA). Albumin and IgG were quantitated by radial immunodiffusion in agar (Meloy Laboratories, Springfield,VA). The
same technique was used to quantitate albumin and IgG
present in serum samples obtained from each patient immediately prior to bronchoalveolar lavage and maintained at
-70°C.
Statistical comparisons. Group data are expressed as
mean L SEM. The statistical computer programs BMDND,
Description of Groups (Strata) with Histogram and Analysis
of Variance and BMDPgD, Missing Value Correlation were
utilized for the data analyses (23).
RESULTS
Analysis of scleroderma lavage cells. Bronchoalveolar lavage of each of our 21 scleroderma patients
yielded a total of 22.3 k 4.4 million cells (mean ?
SEM). Two patients had low cell totals (1.9 and 1.8
million) due to poor recovery of instilled lavage fluid.
Two patients had high cell totals (51.6 and 95.0 million); both had alveolar macrophages with densely
pigmented cytoplasmic inclusions and were presumed
to be smokers (12). The results from these 2 patients
were excluded from further analysis. The cell yield of
the remaining 17 scleroderma patients ranged from 834 million, with a mean of 18.7 ? 1.9 million cells.
Differential cell counts of recovered lavage fluid
showed a greater percentage of polymorphonuclear
leukocytes (PMNs; neutrophils and eosinophils) in the
scleroderma patients than in normal controls. Taking
the upper limit of neutrophils for normal nonsmokers
as 2.2%, 10 of the 19 scleroderma patients had an
abnormally high percentage of neutrophils. Four patients had an abnormally high percentage of eosinophils in their lavage fluid (>3.7%). A total of 11
patients (58%) had increased PMNs in lavage fluid.
These 11 patients (group I) had 12.0 5 3.1% neutrophils, compared with 0.7 -+ 0.2% for patients with a
normal lavage result (group 11). All patients studied
had normal percentages of lymphocytes in lavage
fluid. There was a lower percentage of alveolar macrophages in group 1 than in group 11, secondary to the
relative increase in PMNs in group I.
Group I and group I1 patients did not differ
significantly in disease duration, presence of Raynaud’s phenomenon, extrapulmonary visceral organ
involvement, antinuclear antibodies, or presence of
scleroderma-type capillary morphology (Table 1).
Group 1 patients showed a trend toward more severe
lung disease than group 11 patients. This trend was
manifested by lower vital capacities and diffusion
capacities, as well as more radiographic signs of
advanced interstitial disease. None of the differences
in pulmonary function were statistically significant.
However, if one excludes patients having a disease
duration of I year or less, then patients in group I had a
significantly lower DLco than did patients in group I1
(P < 0.05). Only 1 of the 11 patients having an
abnormal lavage differential had normal chest radiograph findings (Table 2), compared with 5 of 8 patients
in group 11, who tended to have less severe lung
disease, manifested by smaller reductions in vital
capacities and single breath diffusing capacities, as
well as milder radiographic changes (Table 3). Most
did, however, have some degree of pulmonary disease
reflected by abnormal lung volumes, diffusing capacity, or radiograph.
Pulmonary tissue from 2 scleroderma patients
was obtained within 1 week of bronchoalveolar lavage,
in 1 case by open lung biopsy and in 1 case by
1257
LUNG DlSEASE IN SCLERODERMA
Table 2. Pulmonary features of scleroderma patients with abnormal bronchoalveolar lavage cell differentials*
Lavage differential
Patient no.
AIM6
L
Neutrophils
Eos
FVC
FEVJFVC
ILC
RV
DLco
1
73
91
72
89
63
87
77
90
93
80
94
82.623.1
9
1
2
3
3
I
6
1
14
6
25
7
34
9
9
3
2
19
4
12.023.1
4
2
55
46
35
54
78
81
34
98
72
27
52
5727
83
97
86
97
87
88
94
82
59
100
88
87?3
50
51
52
85
83
38
89
82
34
50
6126
45
63
17
22
34
103
67
30
81
58
32
4929
2
3
4
5
6
7
8
9
10
11
MeanfSEM
0
1
0
2.420.8
1
1
0
3
8
5
4
0
2
2.720.7
-
47
103
96
47
82
102
71
50
7157
Radiographic
pattern
Diffuse interstitial
Diffuse interstitial
Diffuse interstitial
Diffuse interstitial
Normal
Basilar interstitial
Basilar interstitial
Basilar interstitial
Basilar interstitial
Diffuse interstitial
Diffuse interstitial
* Lavage differential expressed as % alveolar macrophages (AIM@),lymphocytes (L), neutrophils, eosinophils (Eos). FVC = forced vital capacity;
values are % predicted. FEVj/FVC = I-second forced expiratory volume/forced vital capacity; values are 9% observed. TLC = total lung capacity.
RV = residual volume. DLco = lung diffusing capacity for carbon monoxide: not measurable in patient 10 because her FVC < 1 liter.
autopsy. One patient (patient 17) had mild abnormalities in pulmonary function and focal, rather than
diffuse, interstitial fibrosis (Figures IA and B). No
interstitial neutrophils were detected histologically,
and the lavage cell differential was normal. In contrast,
patient 10 had severe abnormalities in pulmonary
function and diffuse interstitial fibrosis with honeycombed lungs (Figures 2A and B). Alveolar and interstitial neutrophilic inflammation was present, and the
lavage cell differential was distinctly abnormal, showing 19% neutrophils.
Immunoglobulin G content of scleroderma lavage fluid. In view of the association of neutrophils
with elevated immunoglobulins in lavage fluid of certain other interstitial lung diseases (21), lavage IgG
was measured in 10 scleroderma patients. To partially
correct for sampling variability of lavage, albumin
levels were used as a reference for IgG levels, since
albumin is neither synthesized nor selectively degraded within the lung (22). The mean serum IgG/albumin
ratio was 0.59 2 0.10, with a range of 0.22-1.32. The
lavage fluid IgG/albumin ratio was greater than the
corresponding serum ratio in 5 of 10 patients, consistent with a relative increase of IgG in the lower
respiratory tract (Figure 3). This relative increase in
lavage fluid IgG was detected in 3 of 4 patients with an
abnormal cell differential and in 2 of 6 patients with a
normal cell differential. In 3 of the 10 patients studied,
the lavage IgGIalbumin ratio was greater than 3 standard deviations above the mean serum IgG/albumin
ratio. This was attributable to a relative increase in
BAL IgG rather than to a relative decrease in BAL
albumin.
DISCUSSION
This study found significant numbers of PMNs
in the bronchoalveolar lavage fluid of 11 of 19 scleroderma patients studied. Excluding patients with less
than 1 year of symptom duration as too brief for
analysis in this indolent process, the presence of
neutrophils correlated inversely with diffusion capacit y in a statistically significant manner (r = -0.719, P <
0.01). BAL fluid immunoglobulin G levels were also
elevated in these patients. BAL is proposed as an
Table 3. Pulmonary features of scleroderma patients with normal bronchoalveolar lavage cell differentials*
Lavage differential
Patient no.
AIM4
L
Neutrophils
Eos
FVC
FEV l/FVC
TLC
RV
DLco
12
13
14
15
16
17
18
96
96
96
96
99
98
98
98
4
3
0
2
0
2
0
0
0
I
0
0
3
75
37
51
68
95
i4
41
57
69
87
97.0 t 0.4
1.4 2 0.6
80
81
77
95
82
67
93
88
83 C 3
81
48
74
68
66
96
73
71
73 f 5
82
57
51
74
70
53
79
67
67 f 4
19
Mean
f
SEM
* See Table
1
1
1
0
0
1
0
0
2
0.7
2
104
2
0
0.2
0.7
_C
0.4
85
83
75 _C 8
1 footnote for explanations and for definitions of abbreviations.
I05
82
80
74 2 7
Radiographic
pattern
Basilar interstitial
Basilar interstitial
Normal
Normal
Normal
Basilar interstitial
Normal
Normal
SILVER ET AL
1258
A
B
Figure 1. A, Lung tissue from scleroderma patient (patient 17) with normal cellular content of bronchoalveolar lavage fluid, showing focal interstitial fibrosis (hematoxylin and eosin stained, original magnification x
160). B, Higher magnification ( ~ 8 0 0showing
)
absence of interstitial and alveolar neutrophils.
1259
LUNG DISEASE IN SCLERODERMA
A
B
Figure 2. A, Lung tissue from scleroderma patient (patient 10) with 19% neutrophils in bronchoalveolar lavage fluid, showing diffuse interstitial
fibrosis and multiple cystic areas (hematoxylin and eosin stained, original magnification x 80). B, Higher magnification ( x 2 0 0 ) showing alveolar
macrophages (arrowheads) and neutrophils in a distorted lower airspace (long arrow), as well as neutrophils within the interstitium (short arrow).
A blood vessel (V)is also apparent.
addition to the armamentarium for the evaluation of
pulmonary disease in diffuse connective tissue disorders. Its potential for monitoring therapy in pulmonary
scleroderma warrants further study.
The lungs are a frequent target organ in scleroderma (2,8,24), and pulmonary disease is a contributing cause of death in a significant number of patients
(24). Clinical involvement has been reported in approximately 60% of patients with scleroderma. Pathologic studies showing a much higher incidence suggest
that clinical determinants of pulmonary disease may
be relatively insensitive (2,8). Patients with lung involvement usually present with exertional dyspnea, at
which time examination may reveal inspiratory crackles, but these may be late features of the disease (2).
Radiographically, there may be fine, bibasilar, reticular markings, which are usually preceded by abnormal-
ities in pulmonary function (1). Standard clinical tests
of pulmonary function usually reveal a decrease in
lung volume (1-7). An abnormal single breath diffusing
capacity result may precede abnormalities by standard
tests for lung volume. This test is considered a sensitive indicator of lung involvement, but evidence for
pulmonary disease may be present when the diffusing
capacity is normal (1,5,25-28).
The course of lung disease in scleroderma may
be quite variable. Most patients have a gradual deterioration in pulmonary function, characterized by a
gradually increasing restrictive ventilatory defect
(27,28). Others have a rapidly progressive course
resulting in severe interstitial fibrosis. Neither initial
tests of pulmonary function nor clinical or demographic features have been predictive of the subsequent
course (28). In our patients, we attempted to correlate
1260
SILVER ET AL
6
5
BAL
SERUM
I1
-
4i
I
.i'i
..
Abnormal
Normal
LAVAGE CELL DIFFERENTIAL
Figure 3. Bronchoalveolar lavage (BAL) IgG/albumin ratio compared with corresponding serum IgG/albumin ratio in 10 scleroderma patients. A value >1 is indicative of a relative increase of I& in
lavage fluid.
long-term damage as assessed by the single breath
diffusing capacity with BAL findings. There is evidence in other interstitial lung disorders such as sarcoidosis that changes in the DLco accurately reflect
the amount of loss of functioning lung parenchyma
(29-32). In our patients with disease duration of more
than 1 year, the DLco correlated with the percentage
of neutrophils present in lavage fluid. Those patients
with more PMNs may have more diffuse inflammation
with more rapid loss of functioning pulmonary surface
area. Thus, the percentage of PMNs may be a marker
for diffuse inflammatory disease with a more rapidly
progressive course.
The histopathologic features and the associated
physiologic consequences of scleroderma lung disease
resemble those of idiopathic interstitial pulmonary
fibrosis (IPF), but the fibrosis of scleroderma usually
develops over a more protracted course (33,34). In
IPF, the inflammatory process is characterized by the
presence of PMNs and elevated levels of IgG in the
bronchoalveolar lavage fluid (21). Our bronchoalveolar lavage data suggest that a significant percentage of
scleroderma patients have a similar inflammatory
process occurring within the lower respiratory tract.
The presence of inflammatory cells in lavage fluid of
our patients with the most severe interstitial lung
disease suggests that these patients may have a persistent alveolitis which may contribute to the severity of
their lung disease. The presence of such cells in 2
patients with normal pulmonary function is consistent
with the hypothesis that inflammatory alveolitis may
precede fibrosis (35). Normal findings of bronchoalveolar lavage cell analyses in patients with abnormalities in pulmonary function and in chest radiography
suggest that the interstitial fibrotic process may occur
independent of neutrophils or, alternatively, that the
pattern of injury may be cyclic and the number of
PMNs varies over time. Serial studies of scleroderma
patients having abnormal bronchoalveolar cellular
constituents will be required in order to determine
what role such cells play in the pathogenesis of scleroderma lung disease.
It is of interest that the BAL findings in a
significant proportion of scleroderma patients studied
resemble the BAL findings of IPF. Features of connective tissue disorders are present in many patients
with IPF. In the majority, however, the etiology is
unknown, and IPF is viewed by some as a stereotyped
response of the lung to any of a variety of injuries (36).
Studies of the pathogenesis of IPF have centered
around the inflammatory and immune effector cells of
the lung. Various products of these cells have been
postulated as playing a role in the disruption and
fibrosis of the interstitiurn. Neutrophils have been
implicated because of their capacity to modulate collagen synthesis through the release of proteolytic enzymes (37,38) or oxygen radicals (39). The attraction
of neutrophils to the pulmonary interstitium has been
attributed to a neutrophil chemotactic factor derived
from the alveolar macrophage (40). This factor, as well
as others, is produced when the alveolar macrophage
is stimulated. Other products of activated alveolar
macrophages that are capable of regulating collagen
synthesis include fibronectin (41), prostaglandin E2
(42), interleukin-I (43), and a factor which, in the
presence of other growth factors, causes an increase in
fibroblast replication (44).
Although these potential mechanisms have
been described, the actual event responsible for the
prefibrotic inflammation of IPF remains unknown.
Similarly, the primary event responsible for the process of fibrosis of the pulmonary interstitium of scleroderma patients remains undefined. In scleroderma, the
microvasculature is distinctly abnormal; intimal arterial lesions are demonstrable histologically (8,45,46),
and distinctive morphologic microvascular abnormalities are demonstrable in the nailfold capillary (14). It is
conceivable that microvascular injury may play an
important role in the pathogenesis of scleroderma lung
disease. Systematic ultrastructural studies of the
scleroderma lung have not yet been performed, but
LUNG DISEASE IN SCLERODERMA
capillary endothelial cell injury .is a predominant
pathologic feature of interstitial lung disease associated with a variety of other connective tissue diseases
(47), as well as with IPF (48) and several animal
models of IPF (36,49). Abnormal endothelial and endothelial basement membrane function could contribute to the edema and inflammation of the pulmonary
interstitium and alveolus.
Bronchoalveolar lavage is a relatively noninvasive procedure with a generally low complication rate.
In the present study, however, 1 patient experienced a
cardiorespiratory arrest and subsequently died. The
cause of the cardiorespiratory arrest is unknown, but it
may have resulted from laryngospasm and attendant
hypoxia. Since this particular patient had left ventricular dysfunction as well as cor pulmonale, we subsequently broadened our exclusion criteria. We have
elected not to perform bronchoalveolar lavage in patients with systemic or pulmonary hypertension, evidence of left ventricular dysfunction or cor pulmonale
by electrocardiogram or echocardiogram, a room air
Poz <65 tom, or an FVC <1.0 liter.
Bronchoalveolar lavage will facilitate the study
of cells and other constituents of the lower respiratory
tracts of scleroderma patients, which may contribute
to our understanding of scleroderma lung disease. It
may also prove useful in staging the degree of inflammation within the pulmonary interstitium. Furthermore, the use of bronchoalveolar lavage to identify
patients with early, pre-fibrotic inflammatory disease
may allow therapeutic trials aimed at circumventing
end-stage fibrotic disease.
ACKNOWLEDGMENTS
The authors wish to acknowledge Dr. R. Harley and
Dr. J. Upshur for histopathologic studies, K. Prioleau for
technical assistance, and J. Anderson and B. Herbert for
typing the manuscript.
REFERENCES
DeMuth GR, Furstenberg NA, Dabich L, Zarafonetis
CJD: Pulmonary manifestations of progressive systemic
sclerosis. Am J Med Sci 255:94-104, 1968
Weaver AL, Divertie MB, Titus JL: Pulmonary scleroderma. Dis Chest 54:490-498, 1968
Huang CT, Lyons HA: Comparison of pulmonary function in patients with systemic lupus erythematosus.
scleroderma, and rheumatoid arthritis. Am Rev Respir
Dis 932365475, 1966
Catterall M, Rowel1 NR: Respiratory function in progressive systemic sclerosis. Thorax 18:10-15, 1963
1261
5. Hughes DTD, Lee FI: Lung function in patients with
systemic sclerosis. Thorax 18:16-20, 1963
6. Colp CR, Riker J, Williams MH: Serial changes in
scleroderma and idiopathic interstitial lung disease.
Arch Intern Med 132506515, 1973
7. Miller RD, Fowler WS, Helmholz FH Jr: Scleroderma
of the lungs. Proc Staff Meeting Mayo Clin 3456-74,
1959
8. D’Angelo WA, Fries JF, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma).
Am J Med 46:428-440, 1%9
9. Enson Y, Thomas HM, Bosken CH, Wood JA, LeRoy
EC, Blanc WA, Wigger HJ, Harvey RM: Pulmonary
hypertension in interstitial lung disease: relation of vascular resistance to abnormal lung structure. Trans Assoc
Am Phys 88:248-255, 1975
10. Konig G , Lunderschmidt C, Clocuh YP, Scherer U,
Fruhmann G: Klinische Bedeutung der bronchoalveolaren Lavage bei progressiver systemischer Sklerodermie. Dtsch Med Wochenschr 107:723-727, 1982
11. Weinberger SE, Kelman JA, Elson NA, Young RC Jr,
Reynolds HY, Fulmer JD, Crystal RG: Bronchoalveolar
lavage in interstitial lung disease. Ann Intern Med
891459466, 1978
12. Haslam PL, Turton CWG, Lukoszek A, Salsbury AJ,
Dewar A, Collins JV, Turner-Warwick M: Bronchoalveolar lavage fluid cell counts in cryptogenic fibrosing
alveolitis and their relation to therapy. Thorax 35:328339, 1980
13. Subcommittee for Scleroderma Criteria of the American
Rheumatism Association Diagnostic and Therapeutic
Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis
Rheum 23581-590, 1980
14. Maricq HR: Widefield capillary microscopy: technique
and rating scale for abnormalities seen in scleroderma
and related disorders. Arthritis Rheum 24: 1159-1 165,
1981
15. Elias JM: Specific esterases, Principles and Techniques
in Diagnostic Histopathology. Edited by J M Elias. Park
Ridge, NJ, Noyes Publications, 1982, pp 252-255
16. Ferris BG: Recommended standardized procedures for
pulmonary function testing: epidemiology standardization project. Am Rev Respir Dis 118:55-88, 1978
17. Dosman J, Bode F, Urbanetti J, Martin R, Macklem FT:
The use of a helium-oxygen mixture during maximum
expiratory flow to demonstrate obstruction in small
airways in smokers. J Clin Invest 55: 1090-1099, 1975
18. Davis GS, Giancola MS, Costanza ML, Low RB: Analyses of sequential bronchoalveolar lavage samples from
healthy human volunteers. Am Rev Respir Dis 126:611616, 1982
19. Reynolds HY, Newball HH: Analysis of proteins and
respiratory cells obtained from human lungs by bronchial lavage. J Lab Clin Med 8439-573, 1974
20. Koski IR, Poplack DG, Blaese RM: A nonspecific
1262
esterase stain for the identification of monocytes and
macrophages, In Vitro Methods in Cell-Mediated and
Tumor Immunity. Edited by BR Bloom, JR David. New
York, Academic Press, 1976, pp 359-360
21. Reynolds HY, Fulmer JD, Kazmierowski WC, Roberts
WC, Frank MM, Crystal RG: Analysis of cellular and
protein content of bronchoalveolar lavage fluid from
patients with idiopathic pulmonary fibrosis and chronic
hypersensitivity pneumonitis. J Clin Invest 59:165-177,
1977
22. Hunninghake GW, Gadek JE, Kawanami 0, Ferrans
VJ, Crystal RG: Inflammatory and immune processes in
the human lung in health and disease: evaluation by
bronchoalveolar lavage. Am J Pathol 97: 149-198, 1979
23. Dixon WJ: BMDP Statistical Software. Los Angeles,
University of California Press, 1981
24. LeRoy EC: Scleroderma (systemic sclerosis), Textbook
of Rheumatology. Edited by WN Kelley, ED Harris Jr,
S Ruddy, CB Sledge. Philadelphia, WB Saunders, 1981,
pp 1211-1230
25. Wilson RJ, Rodnan GP, Robin ED: An early pulmonary
physiologic abnormality in progressive systemic sclerosis (diffuse scleroderma). Am J Med 36:361-369, 1964
26. Guttadauria M, Ellman H , Emmanuel G, Kaplan D,
Diamond H: Pulmonary function in scleroderma. Arthritis Rheum 20: 1071-1079, 1977
27. Bagg LR, Hughes DTD: Serial pulmonary function in
progressive systemic sclerosis. Thorax 34:224-228, 1979
28. Schneider PD, Wise RA, Hochberg MC, Wigley FM:
Serial pulmonary function in systemic sclerosis. Am J
Med 73:385-394, 1982
29. Marshall R, Karlish AJ: Lung function in sarcoidosis.
Thorax 26:402-405, 1971
30. Marshall R, Smellie H, Baylls JH, Hoyle C, Bates DV:
Pulmonary function in sarcoidosis. Thorax 13:48-58,
1958
31. Sharma OP, Colp C , Williams MH: Pulmonary function
studies in patients with bilateral sarcoidosis of hilar
lymph nodes. Arch Intern Med 117:436-439, 1966
32. Ting EV, Williams MH: Mechanics of breathing in
sarcoidosis of lung. JAMA 192:619-624, 1965
33. Getzowa S: Cystic and compact pulmonary sclerosis in
progressive scleroderma. Arch Pathol 40:99-106, 1945
34. Fulmer JD, Roberts WC, von Gal ER, Crystal RG:
Morphologic-physiologic correlates of the severity of
fibrosis and degree of cellularity in idiopathic pulmonary
fibrosis. J Clin Invest 63:665-676, 1979
35. Crystal RG, Gadek JE, Ferrans VJ, Fulmer JD, Line
BR, Hunninghake GW: Interstitial lung disease: current
concepts of pathogenesis, staging and therapy. Am J
Med 70:542-568, 1981
SILVER ET AL
36. Snider GL: Interstitial pulmonary fibrosis-which cell is
the culprit? Am Rev Respir Dis 127:535-539, 1983
37. Gadek JE, Kelman JA, Fells G, Weinberger SE, Horwitz AL, Reynolds HY, Fulmer JD, Crystal RG: Collagenase in the lower respiratory tract of patients with
idiopathic pulmonary fibrosis. N Engl J Med 301:737742, 1979
38. Phan SH, Schrier D, McGarry B, Duque RE: Effect of
the beige mutation on bleomycin-induced pulmonary
fibrosis in mice. Am Rev Respir Dis 127:456-459, 1983
39. Johnson KJ, Fantone JC 111, Kaplan J, Ward PA: In
vivo damage of rat lungs by oxygen metabolites. J CIin
Invest 67:983-993, 1981
40. Reynolds HY: Lung inflammation: role of endogenous
chemotactic factors in attracting polymorphonuclear
granulocytes. Am Rev Respir Dis 127:S16-S25, 1983
41. Tsukamoto Y, Helsel WE, Wahl SM: Macrophage production of fibronectin, a chemoattractant for fibroblasts.
J Immunol 127:673-678, 1981
42. Goldstein RH, Miller K, Gkassroth J, Linscott R, Snider
GL, Franzblau C, Polgar P: Influence of asbestos fibers
on collagen and prostaglandin production in fibroblast
and macrophage co-cultures. J Lab Clin Med 100:778785, 1982
43. Schmidt JA, Mizel SB, Cohen D, Green I: Interleukin 1 ,
a potential regulator of fibroblast proliferation. J Immunol 128:2177-2182, 1982
44. Bitterman PB, Rennard SI, Hunninghake GW, Crystal
RG: Human alveolar macrophage growth factor for
fibroblasts: regulation and partial characterization. J
Clin Invest 70:806-822, 1982
45. Norton WL, Hurd ER, Lewis DC, Ziff M: Evidence of
microvascular injury in scleroderma and systemic lupus
erythematosus: quantitative study of the microvascular
bed. J Lab Clin Med 71:919-933, 1968
46. Cannon PJ, Hassar M, Case DB, Casarella WJ, Sommers SC, LeRoy EC: The relationship of hypertension
and renal failure in scleroderma (progressive systemic
sclerosis) to structural and functional abnormalities of
the renal cortical circulation. Medicine (Baltimore) 53: 146, 1974
47. Hammar SP, Winterbauer RH, Bockus D, Remington F,
Sale GE, Meyers JD: Endothelial cell damage and
tubuloreticular structures in interstitial lung disease associated with collagen vascular disease and viral pneumonia. Am Rev Respir Dis 127:77-84, 1983
48. Spencer H: Chronic interstitial pneumonia, The Lung.
Edited by AA Liebow, DE Smith. Baltimore, Williams
& Wilkins, 1968, pp 145-150
49. Ryan SF: Experimental fibrosing alveolitis. Am Rev
Respir Dis 105:776-791, 1972
Документ
Категория
Без категории
Просмотров
0
Размер файла
922 Кб
Теги
lavage, interstitial, lung, analysis, disease, bronchoalveolar, scleroderma
1/--страниц
Пожаловаться на содержимое документа