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发表于 2009-3-5 00:02 |只看该作者 |倒序浏览 |打印

作者：Yasushi Adachia,b, Haruki Oyaizua,c, Shigeru Taketanid, Keizo Minaminoa, Kazuyuki Yamaguchic, Leonard D. Shultze, Masayoshi Iwasakia, Minoru Tomitaa, Yasuhiro Suzukia, Keiji Nakanoa, Yasushi Koikea, Ryoji Yasumizua, Makoto Sataf, Noriyuki Hiramaf, Isao Kubotaf, Shirou Fukuharac, Susumu Ikeharaa,b作者单位：aFirst Department of Pathology, Kansai Medical University, Moriguchi-City, Osaka, Japan;bTransplantation Center, Kansai Medical University;cFirst Department of Internal Medicine, Kansai Medical University;dDepartment of Biotechnology, Kyoto Institute of Technology, Sakyo-ku, Kyoto, Japan; ; [- Q: g; k, S" J. m* K' b$ `3 E


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      【摘要】
   We have recently established a new bone marrow transplantation (BMT) method in which bone marrow cells are injected into the intrabone marrow (IBM). In the present study, we used an animal model for emphysema (tight-skin  mice showed emphysema. These results strongly suggest that emphysema in Tsk mice originates from defects of stem cells in the bone marrow.
      【关键词】 Emphysema Treatment Tight-skin mice Intrabone marrow-bone marrow transplantation8 M$ l' h1 k" B( g2 k! a* L
   INTRODUCTION- m/ z1 M' J% ^$ o8 x0 v( o# R
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Emphysema is one of the major factors determining morbidity and mortality in chronic obstructive pulmonary diseases, in which the destruction of the lungs¡¯ gas exchange structures leads to inadequate oxygenation . As it stands, only lung transplantation can provide remediation for severe emphysema.

The tight-skin (Tsk) mouse has a dominant mutation in which the heterozygote (Tsk/ ) mouse shows tight skin with marked hyperplasia of the subcutaneous connective tissue (similar to scleroderma), the augmented growth of cartilage and bone, small tendons with hyperplasia of the tendon sheaths, increased thoracic size, and large distended lungs . As a result, the precise mechanisms underlying the development of emphysema in Tsk mice are still unclear.

Using various autoimmune-prone mice, we have previously shown that conventional allogeneic bone marrow transplantation (BMT) can be used to prevent and treat autoimmune diseases .
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In this study, we show that IBM-BMT can be used to treat emphysema in Tsk mice and that emphysema in these mice can be transferred to normal mice by IBM-BMT, suggesting that autoimmune mechanisms are involved in the development of emphysema in Tsk mice.& ]; b5 V, r# _% k4 L3 g- ~

MATERIALS AND METHODS6 k* K. e" }9 m% H+ u1 e

Mouse Strains& [& n" t: d* f7 g* `

Tsk/  and pa/pa mutant mice on a C57BL/6 (H-2b) background were obtained from the Jackson Laboratory (Bar Harbor, ME, http://www.jax.org). C3H/He (H-2k) mice (C3H mice) were obtained from Japan SLC (Hamamatsu, Sizuoka, Japan, http://www.jslc.co.jp). Because Tsk/  mice are heterozygous of the Tsk and pa mutation, Tsk/  mice were prepared by mating Tsk/  male mice with pa/pa female mice. Tsk/  progeny were identified by their black coat and eye color as well as by their characteristic loss of skin pliability. These mice were maintained in our animal facility under specific pathogen-free conditions and were used at 8¨C10 weeks of age.2 m2 d& `( R/ U3 _5 r5 ^
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Experimental Protocols3 n. _: T: i5 D* p5 ?
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The Tsk/  mice (Tsk mice) (8¨C10 weeks of age) with emphysema were irradiated in fractionated doses (5.5 Gy x 2 = 11 Gy; 4-hour interval) because giving fractionated doses caused less damage in the recipients and was more effective in reconstituting the hemopoietic cells than was a single dose of irradiation . Two groups were prepared as controls. In the first group, Tsk mice were irradiated (5.5 Gy x 2) and transplanted with syngenic whole BMCs (3 x 107) by IBM (Tsk into Tsk). In the second group, C3H/He mice were irradiated (5.5 Gy x 2) and transplanted with syngeneic whole BMCs (3 x 107) by IBM (C3H into C3H). After confirming more than 90% engraftment in peripheral white blood cells, we performed morphological analyses, western blot analyses, and analyses using a confocal microscopy in (C3HTsk) mice.- S% Q% o. Q$ _8 I

For the alternative BMT experiment, we first prepared the lineage-negative (Lin¨C) BMCs to exclude the effects of mature lymphocytes. To prepare the Lin¨C BMCs, BMCs from 6-month-old mice were incubated with biotin-labeled anti-CD3, anti-B220, anti-Gr-1, anti-CD11b, anti-CD11c, and anti-NK 1.1 Abs, followed by incubation with avidin-conjugated magnet beads (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, http://www.miltenyibiotec.com/nn.404,company.html). These Abs were purchased from BD PharMingen (San Diego, http://www.bioresearchonline.com). The cells were passed through a magnetic cell sorting (MACS) midi column (Miltenyi Biotec GmbH) for negative selection of Lin¨C BMCs. These negatively selected BMCs were used as Lin¨C BMCs. Lin¨C BMCs (1 x 106/mouse) from Tsk/  mice were transplanted into irradiated (6 Gy x 2) 8-week-old Tsk/  mice and C3H mice by IBM. Lin¨C BMCs (1 x 106/mouse) from C3H mice were transplanted into irradiated 8-week-old C3H mice by IBM.
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Fixation, Tissue Sampling, and Tissue Preparation

Animals were killed via cervical dislocation, then median sternotomy was performed. To obtain tissue for histological analyses, right heart perfusion was accomplished with calcium- and magnesium-free phosphate-buffered saline (PBS) to clear the pulmonary intravascular space; the tracheas of the mice were cannulated, and the lungs were inflated to approximately 25 cm with neutral-buffered formalin before fixation (neutral-buffered 15% formalin) overnight at 4¡ãC as previously described . Fixed samples of the lung and skin were rinsed in PBS, dehydrated, and embedded in paraffin. Sections (2 µm) were collected on microscope slides and stained with hematoxylin and eosin (H&E) and Masson Fontana for the lungs and skin, respectively. For immunofluorescence study, the lungs were frozen with OCT compound (Tissue-Tek, Miles Inc., Elkhart, IN, http://www.informagen.com).

Morphometric Analysis) s! V6 A. v, F( `/ r3 E" i

The size of alveolar airways was determined by measuring the mean chord length on H&E-stained lungs as previously described . We analyzed at least 120 alveoli per mouse. The length of the lines overlying air space was averaged as the chord length.# U. I- s& E& c/ X% g

Abs and Surface Marker Analysis; J  s$ d5 h& R- a0 F( T. r

Fluorescein isothiocyanate (FITC)-coupled anti-H2Kb and phycoerythrin (PE)-coupled anti-H2Kk Abs from BD PharMingen were used for H-2 typing. Cells were analyzed by a FACScan (Becton Dickinson and Company, Mountain View, CA, http://www.bd.com)." R$ P* |* E8 P" Q. t) s- h

Immunofluorescence Study of Lung+ G4 s4 ?5 l0 P2 [3 X8 e( q
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Frozen sections (2 µm) were stained using FITC-coupled anti-H2Kk plus PE-coupled anti-Mac-1 Abs or FITC-coupled anti-H-2Kk plus anti-cytokeratin followed by PE-coupled anti-rabbit Abs. The samples were observed using an Olympus LSM-GB200 confocal laser microscope (Olympus, Tokyo, http://www.olympus-global.com).5 k. E9 P9 F5 ?9 @  J, M( j1 S8 _
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BMT from Aged Tsk/  Mice to C3H Mice+ l( F# j1 y/ Q, v1 K
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Two-month-old C3H mice were irradiated with fractionated doses (6.0 Gy x 2 = 12 Gy; 4-hour interval). One day after the irradiation, Lin¨C BMCs were prepared, because it has been reported that mature T cells and B cells of Tsk mice induce fibrosis in normal mice , suggesting that contaminated mature immunological cells in the bone marrow might have some effects on emphysema, regardless of engraftment of bone marrow stem cells. The Lin¨C BMCs (1 x 106/mouse) of 6-month-old male Tsk/  mice were directly injected into the tibias of C3H mice (IBM-BMT). The Lin¨C BMCs of Tsk/  mice were prepared as follows: BMCs of Tsk/  mice were incubated with biotin-labeled anti-CD3, anti-B220 Ab, anti-Gr1, anti-Mac 1, anti-NK1.1, and anti-ter119 Abs, followed by incubation with avidin-conjugated magnet beads (Miltenyi Biotec GmbH). The cells were passed through a MACS midi column (Miltenyi Biotec GmbH) for negative selection of Lin¨C BMCs.# T1 d2 m1 `- Z6 O; A' Z
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Statistical Analyses# Z# ^# c+ j7 l& w  C, q

Student¡¯s t test was used to determine statistical significance.
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RESULTS

Amelioration of Emphysema in Tsk/  Mice by IBM-BMT# f2 |! q; [( S1 b, ]. m
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The Tsk mouse is known as an animal model for genetically determined emphysema. Martorana et al. have reported that the enlargement of peripheral lung units in Tsk mice is evident on days 4¨C15 after birth and that the destruction of their lung parenchyma occurs between 15 days and 1 month, rapidly progressing by 2 months . Therefore, we first examined the histology of the lungs of Tsk mice at various ages (Fig. 1). As shown in Figure 1, 8-week-old Tsk mice showed the enlargement of peripheral lung units and the destruction of lung parenchyma (Fig. 1B) in contrast to normal C3H mice (Fig. 1A). More severe lung emphysema was found in the lungs of 12-month-old Tsk mice (Fig. 1C).
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Figure 1. Morphological changes to the lungs of the tight-skin (Tsk) mice and mice after bone marrow transplantation (BMT) and morphological changes to the lungs of C3H mice, Tsk mice, and mice after intrabone marrow (IBM)-BMT. (A): Eight-week-old C3H mice (normal control). (B): Eight-week-old Tsk mice. (C): Twelve-month-old Tsk mice. (D): Six months after IBM-BMT in  mice (8 months old) as described in Materials and Methods. Original magnification: x100 (A-F). Bars = 100 µm.

We next examined whether allogeneic BMT  mice showed a histology similar to that of non-treated C3H mice (Fig. 1D), suggesting that the irradiation for BMT had no harmful effects on the lungs in our experiment.

Figure 2. The effect of IBM-BMT on the chimerism of peripheral blood. Three months after BMT, peripheral blood was obtained and stained with PE-labeled anti-H-2Kb and FITC-labeled anti-H-2Kk antibodies. Abbreviations: BMT, bone marrow transplantation; FITC, fluorescein isothiocyanate; IBM, intrabone marrow; IV, intravenous; PE, phycoerythrin; Tsk, tight-skin.
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We next quantified the alveolar changes by measuring the mean chord length. As shown in Figure 3, C3H mice did not show any changes in alveolar dimensions 6 months after syngeneic IBM-BMT  mice showed a marked reduction in the size of the alveoli.

Figure 3. Evaluation of "mean chord length" in the lungs after IBM-BMT. Mean chord lengths of the lungs were evaluated in the groups of  mice as described in Materials and Methods. Abbreviation: Tsk, tight-skin.
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Recently, it has been reported that BMCs can differentiate into epithelial cells in the lungs  mice but that hematopoietic cells did instead.

Figure 4. Donor-derived epithelial cells and hematopoietic cells in  mice were stained with FITC-coupled anti-H-2Kk plus anti-cytokeratin followed by PE-coupled anti-rabbit antibodies (B). The samples were observed using a confocal laser microscope. Abbreviations: FITC, fluorescein isothiocyanate; PE, phycoerythrin; Tsk, tight-skin.. Z. U4 n+ k7 x
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Amelioration of Skin Structure by IBM-BMT

In general,  mice (Fig. 5). These results suggest that IBM-BMT is effective in treating both scleroderma and emphysema of Tsk mice.* d$ e# K* \& [9 }

Figure 5. Amelioration of the tight skin in Tsk mice by IBM-BMT.  mice shows reduced collagen fibers. Bars = 50 µm. Abbreviations: IBM-BMT, intrabone marrow-bone marrow transplantation; Tsk, tight-skin.; m9 M8 X# S% X7 U7 c8 b5 R

Transfer of Emphysema from Tsk Mice to Normal Mice by IBM-BMT8 S$ E' t/ U6 v; L/ s

To clarify whether emphysema originates from defects of stem cells in the bone marrow, we carried out IBM-BMT from Tsk mice to normal C3H mice using immunocompetent cell-depleted BMCs (Lin¨C cells) of Tsk mice. Six months after IBM-BMT, the  mice (Fig. 6B).- ~. W  X) o' `3 Q7 @1 K9 i

Figure 6. Microscopic findings and evaluation of mean chord length of the lung of  mice. (A): Eight-week-old C3H mice were transplanted with Lin¨C BMCs of 6-month-old C3H mice as described in "Materials and Methods." Six months after transplantation, morphological examinations of the lungs of the mice were performed. (B): Eight-week-old Tsk/  mice were transplanted with Lin¨C BMCs of 6-month-old Tsk/  mice as described in "Materials and Methods." Six months after transplantation, morphological examinations of the lungs of the mice were performed. (C): Eight-week-old C3H mice were transplanted with Lin¨C BMCs of 6-month-old Tsk/  mice as described in "Materials and Methods." Six months after transplantation, morphological examinations of the lungs of the mice were performed. (D): The mean chord length of the lungs of mice transplanted with BMCs was analyzed. Bars = 100 µm. Abbreviation: Tsk, tight-skin.

The size of alveolar airways was determined by measuring the mean cord length on H&E-stained lungs. As shown in Figure 6D, the mean chord length in the lungs of  mice, probably due to the short-term of observation (6 months after IBM-BMT).0 p) m* j6 ^4 Q# q% M) T
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DISCUSSION

The Tsk mouse was first discovered by Green et al.  made a morphological investigation of the Tsk lung. They observed a generalized enlargement of air spaces with markedly thinned or broken alveolar walls and also an increase in the size of the pores of Kohn. These morphological changes were accompanied by increases in total lung capacity and static compliance. On the basis of these findings, they proposed the Tsk mice as a model for genetically determined emphysema.
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In the present study, we have examined whether allogeneic BMT could be used to treat emphysema by promoting new alveogenesis. Histological examination showed that severe emphysematous changes in Tsk mice were dramatically repaired after allogeneic BMT. Emphysema is pathologically defined as a condition of the lung characterized by the abnormal permanent enlargement of the air spaces distal to the terminal bronchiole accompanied by the destruction of alveolar walls. Both an elastolytic process and the inborn defect of connective tissue play a role in the development of emphysema in Tsk mice . We also carried out Western blot analyses using anti-Fin one Ab and have found that the large size of Fbl-1 (418 kD) remains even after IBM-BMT (data not shown). These results suggest that the IBM-BMT can ameliorate the morphological abnormalities of the lungs in Tsk mice regardless of the existence of abnormality of Fib 1.9 k+ x: {, x' X9 E- `+ b& B' `
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It has been reported that Th2 cytokines and TGF-ß play a crucial role in the development of dermalfibrosis in mice ; IL-4R-¨C/¨C Tsk mice did not develop dermalfibrosis, and the deletion of one allele of TGF-ß gene of Tsk mice resulted in diminishing dermalfibrosis. Therefore, it seems likely that Th2 cytokines are related to emphysema. However, IL-4R-¨C/¨C Tsk and TGF-ß /¨C Tsk mice showed emphysema, as seen in Tsk mice. These data suggest that the mechanisms underlying the induction of dermalfibrosis are different from those underlying the development of emphysema.

Recently, it has been reported that bone marrow-derived stem cells can differentiate into various cells, including epithelial cells in the lungs . Therefore, we suppose that normalization of hematopoietic stem cells, not mesenchymal stem cells, could be attributed to the improvement of pulmonary structure." f  A# q: v6 ]8 g7 a
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Finally, we have succeeded in transferring emphysema into normal C3H/He mice by carrying out IBM-BMT using immunocompetent cell-depleted BMCs (Lin¨C cells) of Tsk mice. These findings suggest that emphysema in Tsk mice originates from defects of stem cells in the bone marrow and that autoimmune mechanisms are involved in the development of emphysema, as we previously reported in autoimmune-prone mice , and we have shown this phenomenon in this experiment also. The mice treated with IBM-BMT showed complete chimerism; on the other hand, the mice treated with i.v.-BMT showed mixed chimerism. Moreover, the mice treated with i.v.-BMT did not show the improvement of the pulmonary structure. It is conceivable that residual hematopoietic cells of Tsk mice disturbed the improvement of the pulmonary structure, because the hematopoietic cells of Tsk mice have some immunological abnormalities. Therefore, we think that even i.v.-BMT can improve the pulmonary structure if the complete chimerism is achieved by i.v.-BMT.
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CONCLUSION) D! i" L, ?2 h0 a
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We have shown that allogeneic BMT can be used to not only prevent the progression of emphysema but also improve the structure of the lung.

DISCLOSURES1 g9 k0 H$ S9 d  ~+ x  O
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The authors indicate no potential conflicts of interest.

ACKNOWLEDGMENTS

H.O. and Y.A. contributed equally to this study.
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