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* From the Department of Pathology and Internal Medicine, Nippon Medical School, Tokyo, Japan.
Correspondence to: Yuh Fukuda, MD, Department of Pathology, Nippon Medical School, 1–1-5 Sendagi, Bunkyo-ku, Tokyo 113-0022, Japan; e-mail: fukuda{at}nms.ac.jp
Idiopathic interstitial pneumonia is pathologically classified into acute interstitial pneumonia (AIP), usual interstitial pneumonia (UIP), bronchiolitis obliterans organizing pneumonia (BOOP), nonspecific interstitial pneumonia (NSIP), and so on.1 UIP is clinically progressive and has a bad prognosis. AIP is a severe disease, but some patients recover with a suitable therapy. BOOP and NSIP have a generally good prognosis. We analyzed the mechanism of pulmonary structural remodeling in patients with AIP, UIP, BOOP, and NSIP, especially in the process and characteristics of early fibrotic lesions.
Materials and Methods
The lung specimens were obtained by open-lung biopsy or
video-assisted thoracoscopic surgery in patients with AIP (n = 2),
UIP (n = 4), BOOP (n = 3), and NSIP (n = 4). The methods were
light and electron microscopies, and immunohistochemistry for 
smooth-muscle actin (SMA), keratin, CD8, I-collagen, III-collagen,
IV-collagen, fibronectin, fibronectin receptor (FnR, 5ß1), matrix
metalloproteinase (MMP)-1, MMP-2, MMP-9, membrane type-1 MMP, and
tissue inhibitor of metalloproteinase (TIMP)-2. Gelatin zymography of
lung tissue homogenate of the patients with UIP, BOOP, NSIP, and normal
control subjects was also performed.
Results
In AIP, alveolar walls were diffusely thickened and homogeneous
early fibroses were formed in both interstitium and intra-alveolar
space, which were clearly shown by immunohistochemistry for IV-collagen
(Table 1 ). Mesenchymal cells in early fibrotic lesions were SMA-positive
myofibroblasts and were intensely positive for TIMP-2 compared to MMPs.
But MMP-1 was relatively intensely stained in these myofibroblasts.
Electron microscopy showed that the myofibroblasts located adjacent to
fibrin deposition had well-developed rough endoplasmic reticulum and
actin microfilaments, and showed no figure of collagen
phagocytosis. In AIP, neovascularization was rarely found in
intra-alveolar early fibrosis. Regenerating alveolar epithelial cells
in AIP were less positive for FnR and covered discontinuously the early
fibrotic alveoli.
|
SMA-positive myofibroblasts were TIMP-2
predominant compared to MMPs (Table 1)
.3
Electron
microscopy showed that the myofibroblasts located in intra-alveolar
space had well-developed rough endoplasmic reticulum and actin
microfilaments, and showed rarely the figure of collagen phagocytosis.
Regenerating epithelial cells covering intra-alveolar fibrosis in UIP
were squamous metaplastic cells, cytoplasmic hyaline-laden cells, and
were less positive for FnR and showed the tendency to detach from the
mesenchyme.
Both BOOP and NSIP were CD8-positive T-cell lymphocyte-dominant
interstitial pneumonia. Ultrastructure showed alveolar epithelial cells
associated with infiltrated lymphocytes were detached and basement
membranes were denuded as an early lesion. BOOP3
showed
bud-type intra-alveolar fibroses, and NSIP showed both mural
incorporation-type and bud-type intra-alveolar fibroses (Table 1)
. BOOP
and NSIP showed MMP-predominant fibroblasts in intra-alveolar fibroses,
which were less positive for SMA. Neovascularization in
intra-alveolar fibrosis was conspicuous in both BOOP and NSIP. Collagen
globules that were known to be the late lesions of intra-alveolar
buds4
were observed frequently in the patients with BOOP
and NSIP. Ultrastructurally phagocytosed collagen fibrils were
predominant in fibroblasts in BOOP and NSIP. Conversely, regenerating
epithelial cells covering intra-alveolar fibrosis of BOOP and NSIP were
mainly type II alveolar epithelial cells and were positive for FnR and
showed good adhesion to mesenchyme.
Gelatin zymography showed the latent MMP-9, latent MMP-2, and active MMP-2 in each case of UIP, BOOP, and NSIP, and control. In BOOP,3 the ratio of active-form MMP-2 to the total of MMP-9 and MMP-2 was significantly larger than control cases. NSIP had a pattern similar to BOOP, but was not statistically significant.
Discussion
In UIP, alveolar structures were finally lost and replaced by the bronchiolar epithelial cells with smooth-muscle hyperplasia, which are called true bronchiolization. Early fibrotic lesion in UIP is characterized by TIMP-2–predominant myofibroblasts and marked damage of alveolar epithelial cells.3 TIMP-2 may inhibit the neovascularization and enhance the extracellular matrix deposition.3 Although endogenous factor(s) to enhance the production of TIMP-2 in myofibroblasts are not known yet, they may correlate to the mechanism of progressive fibrosis in UIP. Only AIP showed mesenchymal cell proliferation in both interstitium and intra-alveolar space. TIMP-2 is predominant in mesenchymal cells in early fibrotic lesions in AIP, but MMP-1 is also detected. In AIP, an unknown big insult for the alveoli might be important in the beginning of the disease, but the later stage of regeneration seems to be similar to the general wound healing. This may be the reason why some patients with AIP recover. In BOOP3 and NSIP, bud-type intra-alveolar fibrosis shrunk and became collagen globule. In NSIP, mural incorporation-type changed to loose fibrosis and alveoli were reconstructed. Although temporally homogeneous fibrosis is reported to be characteristic of BOOP and NSIP,5 it does not mean no old fibrosis. Old fibrosis is only inconspicuous in BOOP and NSIP, because the fibroses in BOOP and NSIP are reversible. The fibrotic lesions of BOOP and NSIP have similar characteristics. The difference is that BOOP shows bud-predominant intra-alveolar fibrosis and NSIP shows mural incorporation-predominant intra-alveolar fibrosis. Both BOOP and NSIP are CD8-positive T-cell lymphocyte-dominant interstitial pneumonia and are similar diseases. In addition, bleomycin-induced lung fibrosis, which is frequently used as an experimental model, is not a UIP but an NSIP pattern, because it has both mural incorporation-type and bud-type intra-alveolar fibroses, and shows a tendency to recover.4
In conclusion, UIP is a TIMP-2–predominant, progressive, and irreversible disease. BOOP and NSIP are MMP predominant, reversible, and similar diseases, although BOOP is bud-predominant interstitial pneumonia and NSIP is mural incorporation-predominant interstitial pneumonia.
Footnotes
Abbreviations: AIP = acute interstitial pneumonia;
SMA = smooth-muscle actin; BOOP = bronchiolitis obliterans
organizing pneumonia; FnR = fibronectin receptor; MMP = matrix
metalloproteinase; NSIP = nonspecific interstitial pneumonia;
TIMP = tissue inhibitor of metalloproteinase; UIP = usual
interstitial pneumonia
References
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