(Chest. 1999;116:477-483.)
© 1999
American College of Chest Physicians
Proliferation of Type II Pneumocytes and Alteration in Their Apical Surface Membrane Antigenicity in Pulmonary Sarcoidosis*
Muneharu Hayasaka, MD;
Takayuki Honda, MD;
Keishi Kubo, MD and
Morie Sekiguchi, MD
*
From the Department of Internal Medicine (Drs. Hayasaka, Kubo, and Sekiguchi) and the Department of Laboratory Medicine (Dr. Honda), Shinshu University School of Medicine, Matsumoto, Japan.
Correspondence to: Takayuki Honda, MD, Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621 Japan; e-mail: thondat{at}hsp.md.shinshu-u.ac.jp
 |
Abstract
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Study objective: To evaluate both the proliferation of
type II pneumocytes in the alveolitis associated with pulmonary
sarcoidosis and any alteration in their surface membrane antigenicity.
Materials and methods: We investigated 20
transbronchial lung biopsy (TBLB) specimens from 20 patients with
pulmonary sarcoidosis, 7 TBLB specimens from 7 sarcoidosis patients
without pulmonary involvement, and 19 normal lung specimens, using
colloidal iron stain and immunostaining with anti-Thomsen-Friedenreich
(TF) antigen and anti-surfactant protein-A monoclonal antibodies.
Results: The density of type II pneumocytes was
significantly higher in the pulmonary sarcoidosis specimens ([mean
± SD] 11.1 ± 3.7 per 1 mm alveolar septal length) than in the
nonpulmonary sarcoidosis (7.8 ± 1.3) or normal lung specimens
(7.2 ± 0.8). TF antigen was directly expressed on the apical surface
of some type II pneumocytes in the pulmonary sarcoidosis specimens, but
it was completely masked by sialic acids in the nonpulmonary
sarcoidosis specimens and in the normal lung tissues.
Conclusions: In pulmonary sarcoidosis, type II pneumocytes
proliferated and the antigenicity of the surface membrane was altered.
It is suggested that these type II pneumocytes may be vulnerable to
injury by natural anti-TF antibodies that are cytotoxic when present
with complement. This damage may decrease alveolar surfactant and cause
focal alveolar collapse proceeding to pulmonary fibrosis in some cases
of pulmonary sarcoidosis.
Key Words: alveolitis • sarcoidosis • Thomsen-Friedenreich antigen • type II pneumocyte
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Introduction
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Sarcoidosis
is a chronic inflammatory disease of unknown etiology that is
characterized by the formation of noncaseating epithelioid cell
granulomas in multiple organs.1
In time, the granulomas
either resolve and disappear completely or are converted into scar
tissue.2
In the lung, it is not clear whether the
granulomas mainly progress to extensive pulmonary fibrosis or to
honeycombing. A mild interstitial infiltrate of lymphocytes and plasma
cells occurs frequently.3
T-lymphocytes are integral
participants in the lymphocytic alveolitis observed in the lungs, and
alveolar macrophages stimulate T-cell activation and proliferation in
sarcoidosis.4
5
6
7
The phospholipid concentration in BAL fluid (BALF) is low in patients
with sarcoidosis, which suggests a reduced ability of type II
pneumocytes to synthesize and/or export the constituents of
surfactant.8
The surfactant from these cells alters the
membrane properties of alveolar macrophages and participates in
T-lymphocyte activation,9
and it is possible that
surfactant production and constituents are altered in pulmonary
sarcoidosis.
The Thomsen-Friedenreich (TF) antigen has been observed to be present
selectively on the apical surface of type II pneumocytes in the
lung,10
11
however, it cannot normally be directly
observed because it is completely masked by sialic acids. Sialic acid
may play an important role in protecting type II pneumocytes from
natural anti-TF antibodies, which are cytotoxic in combination with
complement.12
It has been reported that immunotherapy with
TF antigen vaccine is effective for the treatment of breast cancer, in
which TF antigen can be directly observed on the cancer
cells.13
14
15
In situations in which TF antigen is not
masked by sialic acids on type II pneumocytes, these cells may be
vulnerable to attack by natural anti-TF antibodies.
In this study, we examined the mild alveolitis associated with
damage to type II pneumocytes that occurs in sarcoidosis with or
without pulmonary involvement.
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Materials and Methods
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Materials
Twenty-seven lung biopsy specimens were obtained from 27
patients with sarcoidosis by transbronchial lung biopsy (TBLB). The 27
patients who underwent TBLB had been receiving no treatment such as
corticosteroids. These 27 patients were divided into two groups: 20
sarcoidosis patients with pulmonary involvement (pulmonary sarcoidosis
group) and 7 without pulmonary involvement (nonpulmonary sarcoidosis
group). The clinical diagnosis of sarcoidosis was based on evidence of
bilateral hilar lymphadenopathy on chest radiograph and CT scan,
elevation of serum angiotensin-converting enzyme, BALF findings, and
evidence of uveitis compatible with sarcoidosis. The patients in the
pulmonary sarcoidosis group also had histologic findings in their TBLB
specimens and evidence of pulmonary involvement on high-resolution CT
scans of the chest, while the patients in the nonpulmonary sarcoidosis
group had neither. We also used 19 normal lung specimens as the control
(normal group), including 4 TBLB specimens and 15 lung specimens. These
four TBLB specimens were obtained from four patients with a small
nodular lesion in the peripheral lung field. They were undergoing
fiberoptic bronchoscopy for diagnostic purposes, but the specimens were
histologically normal. Ten normal lung specimens were obtained from
necropsies of 10 patients who died without lung disease. Five lung
specimens were taken from five lungs surgically resected for primary
lung cancer; the specimens were taken from areas distant from the
cancerous lesions, and they exhibited a normal alveolar structure.
BAL was performed in 10 patients in the pulmonary sarcoidosis group and
in all members of the nonpulmonary sarcoidosis group using a procedure
described previously.16
BALF from six additional normal
healthy volunteers from whom no lung specimens were taken was used as
the control material.
Light Microscopic Study
Biopsy and necropsy specimens and resected lung tissues were all
fixed in 20% buffered formalin for 24 h. Each specimen was
dehydrated through graded alcohols, cleared in xylene, and embedded in
paraffin. Serial sections 3 µm thick were subjected to hematoxylin
and eosin staining and to cacodylic acid colloidal iron (CI) staining
(pH 2.5), and they were immunostained with anti-TF monoclonal antibody
(MoAb [DAKO; Grostrup, Denmark]) and anti-surfactant protein-A
(anti-SP-A) MoAb (a gift from Dr. Toyoaki Akino, Department of
Biochemistry, Sapporo Medical University, Sapporo, Japan).
For CI staining, tissue sections were incubated for 10 min in a
cacodylic iron solution. Cacodylic acid iron colloidal stock solution
(Wako Pure Chemical; Osaka, Japan) was diluted five times with 0.1
mol/L cacodylic acid buffer, and the resulting solution was
adjusted to pH 2.5 with 1N HCl. Pretreatment by sialidase digestion
(from Arthrobactor ureafaciens; Nakarai Chemicals; Kyoto,
Japan [1 U/mL in 0.05 mol/L phosphate buffer; pH 7.0]) was interposed
at 37°C for 4 h. CI binding sites were visualized with the aid
of potassium ferrocyanide solution.17
These slides were
counterstained using nuclear fast red.
Other sections for immunostaining were incubated in 0.3% hydrogen
peroxide in methanol for 30 min to inhibit endogenous peroxidase
activity. Some of the sections for anti-TF staining were pretreated by
sialidase digestion at 37°C for 4 h. They were then incubated in
phosphate-buffered saline (PBS) containing 1% bovine serum albumin and
MoAb (anti-TF 1:100; anti-SP-A 1:100) at 4°C for 18 h.
After rinsing in PBS, the sections were incubated in solutions
containing horseradish peroxidase-conjugated goat anti-mouse IgG
antibody (diluted to 1:100 in PBS). After further rinsing in PBS,
antibody binding sites were visualized with the aid of a solution
containing 0.02% 3,3'diaminobenzidine (Wako Pure Chemical) and 0.005%
hydrogen peroxide in phosphate buffer. Counterstaining was carried out
with hematoxylin.
Immunoelectron Microscopic Study
Normal lung tissues were immediately cut into small pieces
and placed in 4% paraformaldehyde for 18 h. The fixed lung
tissues were washed in PBS containing 10%, 15%, and 20% sucrose.
They were embedded in OCT compound (Miles Pharmaceutical;
Naperville, IL) and frozen in dry ice-acetone. Cryostat sections 6 µm
thick were pretreated by sialidase digestion as described above, then
immersed in PBS containing bovine serum albumin and incubated with
anti-TF antibody (1:100) at 4°C for 18 h. After being rinsed in
PBS containing 10% sucrose, the sections were incubated in solutions
containing horseradish peroxidase-conjugated goat anti-mouse IgG
antibody (diluted to 1:100 in PBS) and fixed with 1% glutaraldehyde
for 5 min. After further rinsing, antibody binding sites were
visualized with the aid of a solution containing 0.02%
3,3'diaminobenzidine and 0.005% hydrogen peroxide in phosphate buffer.
The sections were post-fixed with 1% osmium tetroxide in PBS for 30
min, dehydrated through a graded ethanol series, and embedded in Epon
812. Ultrathin sections were examined using a JEM-1010 electron
microscope (Jeol [UK] Ltd; Herts, UK).
Density of Type II Pneumocytes
Five areas of 0.58 x 0.44 mm were randomly selected on each
of the slides stained with anti-TF antibody following sialidase
digestion. The numbers of type II pneumocytes were counted on the thin
alveolar septa, which appeared to maintain an almost normal alveolar
structure. Those on thick alveolar septa and those on the connective
tissue near bronchioles were excluded. The same areas were photographed
using a digital camera (Sony DKC 5000; Sony; Tokyo, Japan), and the
total length of each alveolar septum was measured using NIH-Image
1.60/pcc (National Institutes of Health; Bethesda, MD) obtained from
sippy.nimh.nih.gov via anonymous file transfer protocol. The
density of type II pneumocytes was expressed as the number per 1 mm of
alveolar septal length.
Statistical Analysis
Data are expressed as the mean ± SD. Results were considered
to be statistically significant when the probability value was < 0.05
(unpaired t test).
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Results
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Clinical and BALF Findings
Clinical and BALF data for the pulmonary and nonpulmonary
sarcoidosis patients are summarized in Table 1
. BALF from six normal volunteers was used as a normal control. The
lymphocyte count in BALF was significantly increased in the pulmonary
sarcoidosis group in comparison with both the nonpulmonary sarcoidosis
group and the normal volunteers. There were also significant
differences in the CD4+/CD8+ ratio between each of the sarcoidosis
groups and the normal volunteers.
Light Microscopic Findings
The results of CI staining and immunostaining in the sarcoidosis
patients are summarized in Table 2
.
Nonpulmonary Sarcoidosis Specimens and Normal Lung Specimens:
The type II pneumocytes showed similar staining characteristics in
these two groups. CI added a strong or moderate blue coloration to the
apical surface of all type II pneumocytes in these specimens (Fig 1
, left, A), and this ability to stain was abolished by
pretreatment involving sialidase digestion. Anti-TF antibody stained no
cells in these specimens when pretreatment by sialidase digestion was
not employed; however, the apical surface of all type II pneumocytes
was stained selectively after sialidase digestion (Fig 1
, center,
B). Anti-SP-A antibody, on the other hand, stained the cytoplasm
of type II pneumocytes (Fig 1
, right, C) and some alveolar
macrophages. Anti-SP-A-positive type II pneumocytes mostly matched
those that were reactive for anti-TF.
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Figure 1. Type II pneumocytes in a normal lung specimen
(original magnification, x400). The apical surface of the type II
pneumocytes is stained blue by CI staining (left, A) and
brown by immunostaining with anti-TF antibody (following pretreatment
by sialidase digestion; center, B). The cytoplasm of
type II pneumocytes is positive for anti-SP-A staining (right,
C).
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Pulmonary Sarcoidosis Specimens:
The intensity of CI staining on type II pneumocytes was decreased
moderately in eight patients and strongly in 10 patients compared with
the specimens from the other groups. In the remaining two patients, CI
showed the same reactivity as in the other groups. In the absence of
pretreatment by sialidase digestion, anti-TF antibody stained none,
< 1%, 1 to 5%, 5 to 10%, and 10 to 30% of type II pneumocytes in
4, 4, 8, 1, and 3 specimens, respectively, from the pulmonary
sarcoidosis group (Fig 2
, top, A). After sialidase digestion, all type II pneumocytes
from this group were stained with anti-TF antibody stain (Fig 2
,
center, B). Anti-SP-A antibody, on the other hand, stained
the cytoplasm of type II pneumocytes strongly in eight specimens (Fig 2
, bottom, C), moderately in six specimens, and weakly in
six specimens.
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Figure 2. TBLB specimen from a patient with pulmonary
sarcoidosis (original magnification, x100). Only some type II
pneumocytes are stained by anti-TF antibody in the absence of
pretreatment by sialidase digestion (top, A), but all
are stained after sialidase digestion (center, B). Their
cytoplasm is positive for anti-SP-A antibody (bottom,
C).
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Electron Microscopic Findings
The luminal surface and microvilli of type II pneumocytes were
selectively stained with anti-TF antibody stain after sialidase
digestion (Fig 3
). No other cells in the alveolar region were positive for anti-TF.
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Figure 3. Electron micrograph of a type II pneumocyte in a
normal lung specimen pretreated with sialidase (original magnification,
x3,000). The apical surface of the type II pneumocyte is stained by
anti-TF antibody.
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Density of Type II Pneumocytes:
The density of type II pneumocytes was 6.9 ± 0.7 in the necropsy
specimens, 7.8 ± 1.0 in the surgical specimens, and 7.2 ± 0.8 in
the normal TBLB specimens. There were no significant differences among
these values (p > 0.05; Table 3
). Because the density was not correlated with age (Fig 4
), gender, or smoking status (Table 4
), we took the value of 7.2 ± 0.8 for the entire group of 19 normal
specimens as the normal density.
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Figure 4. There was no significant correlation between the
patient's age and the density of type II pneumocytes (expressed as
number per 1 mm of alveolar length) in normal lung tissues.
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The density in the pulmonary sarcoidosis specimens was 11.1 ± 3.7, a
value significantly higher than that found for both the nonpulmonary
sarcoidosis specimens (7.8 ± 1.3) and the normal specimens
(7.2 ± 0.8; Table 5
).
In six specimens from six pulmonary sarcoidosis patients, only a few
areas could be analyzed (one, two, and three areas in one, two, and
three patients, respectively) because the TBLB specimens obtained from
them were very small and contained a few areas exhibiting an almost
normal alveolar structure.
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Discussion
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The density of type II pneumocytes was significantly higher in
pulmonary sarcoidosis than in either nonpulmonary sarcoidosis or normal
lung tissue. Proliferation of type II pneumocytes may be one of the
most sensitive pathologic findings in the reparative phase of
alveolitis18
and may indicate preceding alveolar damage in
pulmonary sarcoidosis even if there is no thickening and/or edema of
the alveolar septum and no infiltration of inflammatory cells.
In pulmonary sarcoidosis, proliferation of type II pneumocytes without
a change in the alveolar structure was sometimes observed around
granulomas. However, it has previously been difficult to identify a
slight proliferation of type II pneumocytes in slowly progressive
interstitial lung diseases, including sarcoidosis and idiopathic
pulmonary fibrosis, because there has not been a method enabling
investigators to count type II pneumocytes with any accuracy.
Immunostaining with anti-TF antibody after sialidase digestion
selectively stains type II pneumocytes,10
and use of this
sequence enabled us to count their number under the light microscope.
While SP-A has also been used as a marker of type II pneumocytes, the
intensity of immunostaining with anti-SP-A is dependent on the amount
of surfactant stored in the cytoplasm, and some of these cells are not
stained at all with anti-SP-A. Consequently, TF antigen is a better
marker for this purpose than SP-A.
Calculating the density of type II pneumocytes per 1 mm of alveolar
septal length is a more sensitive and reliable way of counting type II
pneumocytes than calculating the number per alveolus or in a fixed
square on the slide. Because the lung is a sponge-like tissue, tissue
fixation markedly affects its volume and thus alters the number of type
II cells per fixed square. A count per alveolus has also been used,
however, it is difficult to count the number of alveoli because they
vary considerably in size and do not form complete circles. Our counts
of type II pneumocytes per 1 mm of alveolar septal length in TBLB,
necropsy, and surgical specimens gave values of 7.2 ± 0.8,
6.9 ± 0.7, and 7.8 ± 1.0, respectively. There were no significant
differences between these values. The SD is smaller than might be
expected, so type II pneumocytes may be spaced in a fairly regular
fashion along the alveolar wall. On the basis of our data, we can use
7.2 ± 0.8 per 1 mm of alveolar septal length as the normal value for
biopsy specimens processed in the ordinary way.
As mentioned above, proliferation of type II pneumocytes is thought to
indicate alveolitis in pulmonary sarcoidosis. This notion is supported
by our finding that the number of lymphocytes in BALF from pulmonary
sarcoidosis patients was significantly higher than in BALF from either
nonpulmonary sarcoidosis patients or normal volunteers. A mild
interstitial infiltrate of lymphocytes and plasma cells occurs
frequently in patients with sarcoidosis, especially around the
granulomas.3
The formation of granulomas in sarcoidosis is
possibly related to lymphocytic alveolitis caused by mild alveolar
damage.
TF antigen was directly observed on the surface of some type II
pneumocytes in the present pulmonary sarcoidosis specimens. We
previously reported that the intensity of CI staining was decreased on
type II pneumocytes in sarcoidosis, indicating a decrease in sialic
acids.19
While the direct observation of TF antigen
supports this finding, it is not yet clear whether the sialic acids on
the apical surface are removed or inhibited to add to TF
antigen. Either way, the antigenicity of the apical surface of
type II cells was certainly changed in pulmonary sarcoidosis.
The type II pneumocytes in the normal lung have a thick surface coat
containing sialic acids,20
21
and these acids may play an
important role in protecting them from natural anti-TF antibody, which
is cytotoxic when present with complement.12
Direct
expression of TF antigen is normally restricted to the parenchyma of
the brain and the spermatocytes in the testes, sites that are not
accessible to serum antibodies.11
However, it has also
been reported that immunotherapy with TF antigen vaccine is effective
for the treatment of breast cancer, in which TF antigen is directly
observed on the carcinoma cells.14
In pulmonary
sarcoidosis, the type II pneumocytes on which TF antigen can be
directly observed are presumably vulnerable to injury by natural
anti-TF antibody. Such damage to type II pneumocytes might adversely
affect the alveolar surfactant system and cause alveolitis with or
without focal collapse of alveoli.
It has been reported that sialidase activity is higher in BALF
from patients with sarcoidosis than in that from normal
volunteers.22
While some bacteria23
24
and
viruses25
26
can produce sialidase, there has been no
report of sialidase production by Mycobacterium tuberculosis
or Propionibacterium acnes, which are thought to be
candidates for the pathogens of sarcoidosis.27
28
Polymorphonuclear neutrophils, lymphocytes, fibroblasts, and alveolar
macrophages can also produce sialidase,23
29
but it is not
yet clear what acts as the source of the elevated sialidase activity
seen in BALF from patients with pulmonary sarcoidosis.
In conclusion, we postulate that alveolitis in pulmonary sarcoidosis
may be caused by an immune reaction, with the natural anti-TF
antibodies acting in combination with an elevation in sialidase
activity in the alveoli. Mild and continuous damage to type II
pneumocytes may lead to a decrease in surfactant in the alveoli,
causing alveolar collapse and, in some cases, may also lead to the
development of pulmonary fibrosis.
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Footnotes
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Abbreviations: BALF = BAL fluid; CI = colloidal
iron; MoAb = monoclonal antibody; PBS = phosphate-buffered saline;
SP-A = surfactant protein-A; TBLB = transbronchial lung biopsy;
TF = Thomsen-Friedenreich
Received for publication August 14, 1998.
Accepted for publication March 2, 1999.
|
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Abstract
Introduction
