Biomedical subjects

H Miyazaki

Publications and source records attributed to H Miyazaki.

At least 199 records · Page 11Linked to original sources

PubMed1998

Pituitary-dependent expression of the testicular angiotensin II receptor and its subtypes in rats.

Angiotensin II (AT2) has been implicated in the growth and/or differentiation of its target tissues. In the present study, testicular AT2 receptor and its subtypes in hypophysectomized rats were examined using quantitative in vitro autoradiography and Northern blot analysis in an attempt to determine possible involvement of pituitary hormones in their expression. Prepubescent (3 weeks of age) male Sprague-Dawley rats underwent hypophysectomy or sham operation. From 10 days thereafter, they were treated with vehicle, growth hormone, human chorionic gonadotrophin or human menopausal gonadotrophin for 10 days. Testicular AT2 receptors were labelled with 125I-[Sar1,Ile8] AT2 and differentiated into its subtypes (AT1 and FAT2) according to their susceptibility to AT1 (losartan, 5 microM) and AT2 (CGP42112B, 1 microM) antagonists. Hypophysectomy led to a marked increase in AT2 receptor concentration (sham-operated rats: 0.7 +/- 0.2 fmol/mg protein, hypophysectomized rats: 2.5 +/- 0.6 fmol/mg protein, mean +/- SEM, n = 11-12, p < 0.01) with predominant occurrence of AT1 receptors. Both human chorionic gonadotrophin and human menopausal gonadotrophin decreased testicular AT2 receptor concentration, whereas growth hormone did not affect AT2 receptor expression. Northern blot analysis revealed both testicular AT1 and AT2 receptor mRNA expression to be significantly increased after hypophysectomy and reduced by gonadotrophin treatment. These results suggest that the expression of testicular AT2 receptors is regulated by pituitary gonadotrophins and that AT2 may play a role in testicular growth and/or differentiation.

Angiotensin II↗

PubMed1998

Gene expression and roles of angiotensin II type 1 and type 2 receptors in human adrenals.

Although stimulation of aldosterone secretion is one of the functions of angiotensin II, the gene expression and biological significance of the angiotensin II receptor subtypes, AT1 and AT2, in the human adrenal have not been characterized. We therefore investigated the transcription levels of the receptor subtype genes and their roles in regulation of steroid secretion by human adrenals. The expression of AT1 and AT2 receptor mRNA was assessed by reverse transcription-polymerase chain reaction followed by Southern blot analysis in normal adrenocortical tissues (n = 6) and a series of adrenal tumour tissues: aldosterone-producing adrenocortical adenoma (n=6), Cushing's syndrome (n = 6) and pheochromocytoma (n = 6). The role of the two receptor subtypes in steroid secretion in vitro was examined by incubating the tissue with angiotensin II(1 microM) with or without the selective AT1 antagonist CV-11974 (1 microM). Both AT1 and AT2 receptor mRNA transcripts were demonstrated in all of the human adrenal tissues tested. Angiotensin II-induced aldosterone secretion was suppressed 50% upon the addition of CV-11974. The selective AT2 agonist CGP-42112 increased aldosterone secretion by 55% over the control, which was not suppressed by CV-11974. Angiotensin II and CGP-42112 did not affect cortisol secretion. These results suggest that both AT2 and AT1 receptors may be involved in the regulation of aldosterone secretion and tumorigenesis of the human adrenals.

Adenoma↗

PubMed1998

Induction of metallothionein isoforms in rat hepatoma cells by various anticancer drugs.

The induction of metallothionein (MT) isoforms (MT-1, -2) by anticancer drugs was investigated in cultured rat hepatoma H4 II E C3 cells. The steady-state expression of MT-1 mRNAs was higher than that of MT-2 mRNAs. During incubation of the cells with various anticancer drugs, namely, adriamycin, epirubicin, cis-diamminedichloroplatinum(II) (CDDP), and cis-diammine(1, 1-cyclobutyldicarboxylato)platinum(II), both MT-1 and MT-2 mRNAs were coordinately inducible: the levels of isoMT mRNA reached a maxim of approximate by 6-fold at 3 h. Immunofluorescent studies revealed that the cytosolic fluorescence in the cells exposed to 1 microM CDDP for 48 h was more intensified than that in the untreated cells. Transfer of antisense oligonucleotides resulted in marked reduction of isoMT mRNA, and upon exposure to 5 microM CDDP for 48 h, the viabilities of these cells dropped to 25.8% of the controls. These results indicate that anticancer drugs are potent inducers of MT isoforms in hepatoma cells and that a decrease in cellular MTs enhances the susceptibility of hepatoma cells to CDDP. Thus, we conclude that endogenous MTs play a role in determining the sensitivity or resistance of cancer cells to clinically important anticancer agents.

Animals↗

PubMed1998

Effects of follicle-stimulating hormone on endothelin receptors in cultured rat ovarian granulosa cells.

Two subtypes of the endothelin (ET) receptor (ETA and ETB) were studied in cultured ovarian granulosa cells. Immature 21-day-old female Wistar-Imamichi rats were implanted with diethylstilbestrol (DES) pellets for 5 days and granulosa cells were collected by repeated puncturing. Viable cells (2.5 or 5 x 10(5)) were cultured with 50--400 ng/ml of ovine NIH follicle-stimulating hormone (FSH) in the presence or absence of [125I-Tyr13]ET-1 (50 pM) in 1 ml McCoy's 5a medium for 72 h. FSH gradually increased the [125I-Tyr13]ET-1 binding to granulosa cells, whereas FSH-untreated granulosa cells had no significant changes. The dose of 200 ng/ml of FSH was most effective for [125I-Tyr13]ET-1 binding for 48-h culture, thereafter revealing a plateau. After 48 h of culture with 200 ng/ml of FSH, granulosa cells were further incubated with [125I-Tyr13]ET-1 (10 pM-1 nM) and/or [125I]IRL1620, the selective ETB receptor agonist (10 pM-1 nM) for 2 h for equilibrium study, and then the dissociation constant and the maximal binding capacity between receptors and ligands were determined by saturation curve and Scatchard plot analysis. ETA + ETB, ETB, and ETA (sites/cells) showed a 4.4-, 2.6-, and 7.5-fold increase, respectively. As for steroidogenesis, ET-1 (100 nM) or ET-3 (100 nM) suppressed FSH-induced progesterone and 17 beta-estradiol production. These results indicate that FSH upregulates both ETA and ETB receptors in DES-treated immature rat granulosa cells, with no significant differences between ET-1 and ET-3, and that ET-1 or ET-3 suppresses FSH-induced steroidogenesis. ETs may affect the granulosa cell function through the ETA and ETB receptors, and the increase in amount of ET binding does not reflect ET effects on granulosa cell function. The ET receptor plays an important role in the development of the ovary.

Animals↗

PubMed1998

A study on epidermal proliferation ability in cholesteatoma.

With the objective of estimating proliferation ability of epidermis of middle ear cholesteatoma, the difference in proliferating cell nuclear antigen (PCNA) staining between the skin of the bone region of the external ear canal (control skin) and cholesteatoma epidermis and the effects on PCNA staining of subepidermal inflammatory cell infiltration of cholesteatoma were immunohistochemically studied using an antibody against PCNA. Transforming growth factor-alpha (TGF-alpha) is known to promote epidermal proliferation based on autocrine mechanism. But it is not clear that cholesteatoma epidermis is actually in the state of hyperproliferation under the effect of this growth factor. To estimate the effect of TGF-alpha on epidermal proliferation ability, the authors compared the location of PCNA and TGF-alpha in the same specimen. Unlike the control skin, not only epidermal basal cell layer and suprabasal cell layer, but also more superior layers were found to have high levels of PCNA staining in the epidermis of cholesteatoma. However, in the same cholesteatoma epidermal tissue, the PCNA staining was varied and the difference was ascribable to subepidermal cell inflammation. It appeared that the proliferation ability was high in regions where subepidermal inflammatory cell infiltration was severe. These differences in microenvironment are inferred to greatly affect proliferation ability of cholesteatoma epidermis.

Adult↗

PubMed1998

Update on thrombopoietin in preclinical and clinical trials.

Thrombopoietin, also termed the c-Mpl ligand, is a lineage-dominant hematopoietic factor that primarily regulates megakaryopoiesis and thrombopoiesis. Treatment of normal animals with recombinant human megakaryocyte growth and development factor, a truncated molecule of the c-Mpl ligand, which is modified with polyethylene glycol (PEG-rHuMGDF), and glycosylated recombinant thrombopoietin stimulates the expansion of bone marrow megakaryocytes and their progenitors, and greatly enhances the production of morphologically and functionally normal platelets. In contrast, this cytokine has only minimal effects on peripheral leukocyte and erythrocyte counts. In myelosuppressed animals, PEG-rHuMGDF or glycosylated thrombopoietin accelerates multilineage hematopoietic recovery effectively improving thrombocytopenia and, in most models, leukopenia (or neutropenia) and anemia. In addition to daily multiple injections, even a single injection of PEG-rHuMGDF after myelosuppressive treatment is fully effective for hematopoietic recovery. In clinical trials, PEG-rHuMGDF or glycosylated recombinant human thrombopoietin potently stimulates thrombopoiesis in cancer patients before chemotherapy. The administration of PEG-rHuMGDF alone or in combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) reduces the duration of severe thrombocytopenia and in some cases platelet nadirs in patients with advanced cancers after dose-intensive chemotherapy. The recombinant hormone is well-tolerated with little drug-related toxicity.

Animals↗

PubMed1998

Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis.

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or non-parenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.

Adult↗

PubMed1998

Regulation of hepatic thrombopoietin production by portal hemodynamics in liver cirrhosis.

OBJECTIVE: This study was designed to clarify how thrombopoietin (TPO) functions in and, to some extent, causes thrombocytopenia complicating liver cirrhosis and portal hypertension. METHODS: Our study population consisted of 19 cirrhotic and six noncirrhotic patients who underwent percutaneous transhepatic portography (PTP) and hepatic venography. RESULTS: The platelet counts of the cirrhotic patients were significantly lower than those of the noncirrhotic patients (8.7 +/- 4.1 vs 17.4 +/- 7 x 10(4)/microl; p < 0.01). The flow direction in the splenic vein was confirmed by PTP. Ten hepatofugal and nine hepatopetal flow directions in the splenic vein were noted among the cirrhotics. The hepatofugal group showed lower portal venous pressure (20 +/- 10 vs 32 +/- 4 cm H2O; p < 0.01) than the hepatopetal group and had a higher incidence of hepatic encephalopathy (six of 10 vs zero of nine; p < 0.01). The hepatic vein-portal difference in TPO did not differ substantially between the cirrhotics and noncirrhotics (0.12 +/- 0.04 vs 0.24 +/- 0.07 fmol/ml). Comparisons of this value among the three groups showed the TPO difference to be lowest in the hepatofugal group (hepatofugal: 0.04 +/- 0.03, hepatopetal: 0.21 +/- 0.07, noncirrhotic: 0.24 +/- 0.07; p < 0.05). CONCLUSIONS: Our findings suggest that TPO production in the cirrhotic liver is regulated by the portal blood supply to the liver. Thus, portal hemodynamics may play a critical role in the development of thrombocytopenia.

Aged↗

PubMed1998

Further examination of various administration protocols of pegylated recombinant human megakaryocyte growth and development factor on thrombocytopenia in myelosuppressed mice.

Thrombopoietin (TPO) is the recently isolated lineage-dominant hematopoietic factor that plays a pivotal role in the regulation of megakaryocytopoiesis and thrombopoiesis. In vivo studies have shown that daily multiple injections of pegylated human megakaryocyte growth and development factor (PEG-rHuMGDF), a truncated molecule related to human TPO, modified with polyethylene glycol, greatly improve thrombocytopenia and in most cases anemia and neutropenia in myelosuppressed animal models. In this study, we further examined various administration protocols of PEG-rHuMGDF on thrombocytopenia in mice treated with a combination of irradiation and carboplatin. After the myelosuppressive treatment on Day 0, mice received the same amount of PEG-rHuMGDF beginning on Day 1 by a single, 3 times (on alternate days), or 7 day daily administration. A single injection of PEG-rHuMGDF significantly reduced the severity and duration of thrombocytopenia and anemia with a concomitant accelerated recovery of megakaryocytic and erythroid progenitors in the bone marrow, similar to the 2 other administration protocols. As the start of a single injection of PEG-rHuMGDF was delayed, its therapeutic effects were attenuated. These results indicate that an administration of PEG-rHuMGDF at an earlier time after the myelosuppressive treatment is necessary to improve thrombocytopenia and anemia.

Animals↗

PubMed1998

A comparison of DAI scores and characteristics of occlusal traits in three ethnic groups of Asian origin.

The Dental Aesthetic Index (DAI) is an orthodontic index based on socially defined aesthetic standards. The primary aim of this study was to compare the prevalence of malocclusion using the DAI among three ethnic groups of Asian origin; Japanese, Chinese in Taiwan and Native Americans with white Americans. A secondary goal was to consider the possibility that genetic factors might be the cause of the characteristics of malocclusion in the ethnic groups of Asian origin. Malocclusion was evaluated in 1029 Japanese and 176 Chinese in Taiwan students utilising the DAI, and the findings were compared with those of Native Americans and white Americans. The DAI values of Japanese and Native Americans were significantly higher than those of Chinese in Taiwan and white Americans. The mean DAI values showed no common tendency among the three ethnic groups. The characteristics of malocclusion in each ethnic group were also evaluated by analysis of each of the 10 DAI component scores. The results revealed common characteristics of malocclusion in the three ethnic groups of Asian origin using white Americans as the standard. The findings in the present study suggest the possibility that genetic factors might have an influence on the characteristics of malocclusion.

Adolescent↗

PubMed1998

Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata.

Sequential Candida glabrata isolates were obtained from the mouth of a patient infected with human immunodeficiency virus type 1 who was receiving high doses of fluconazole for oropharyngeal thrush. Fluconazole-susceptible colonies were replaced by resistant colonies that exhibited both increased fluconazole efflux and increased transcripts of a gene which codes for a protein with 72.5% identity to Pdr5p, an ABC multidrug transporter in Saccharomyces cerevisiae. The deduced protein had a molecular mass of 175 kDa and was composed of two homologous halves, each with six putative transmembrane domains and highly conserved sequences of ATP-binding domains. When the earliest and most azole-susceptible isolate of C. glabrata from this patient was exposed to fluconazole, increased transcripts of the PDR5 homolog appeared, linking azole exposure to regulation of this gene.

AIDS-Related Opportunistic Infections↗

PubMed1998

Involvement of prolonged ras activation in thrombopoietin-induced megakaryocytic differentiation of a human factor-dependent hematopoietic cell line.

Thrombopoietin (TPO) is a hematopoietic growth factor that plays fundamental roles is both megakaryopoiesis and thrombopoiesis through binding to its receptor, c-mpl. Although TPO has been shown to activate various types of intracellular signaling molecules, such as the Janus family of protein tyrosine kinases, signal transducers and activators of transcription (STATs), and ras, the precise mechanisms underlying TPO-induced proliferation and differentiation remain unknown. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into F-36P, a human interleukin-3 (IL-3)-dependent erythroleukemia cell line, and the effects of TPO on the c-mpl-transfected F-36P (F-36P-mpl) cells were investigated. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. Dominant-negative (dn) forms of STAT1, STAT3, STAT5, and ras were inducibly expressed in F-36P-mpl cells, and their effects on TPO-induced proliferation and megakaryocytic differentiation were analyzed. Among these dn molecules, both dn ras and dn STAT5 reduced TPO- or IL-3-induced proliferation of F-36P-mpl cells by approximately 30%, and only dn ras could inhibit TPO-induced megakaryocytic differentiation. In accord with this result, overexpression of activated ras (H-rasG12V) for 5 days led to megakaryocytic differentiation of F-36P-mpl cells. In a time course analysis on H-rasG12V-induced differentiation, activation of the ras pathway for 24 to 28 h was required and sufficient to induce megakaryocytic differentiation. Consistent with this result, the treatment of F-36P-mpl cells with TPO was able to induce prolonged activation of ras for more than 24 h, whereas IL-3 had only a transient effect. These results suggest that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation.

Cell Differentiation↗

PubMed1998

Beta-adrenergic receptor number in human lymphocytes is inversely correlated with aerobic capacity.

In the present study, the relationships between beta-adrenergic receptor (beta-AR) expression and aerobic capacity evaluated by maximal oxygen consumption (.VO2max) and oxygen consumption level at ventilatory threshold (.VO2@VT) were investigated. Seventeen physically untrained and 25 trained men participated in the study. After supine resting, the peripheral blood was sampled for preparation of lymphocytes, the model cell used to analyze the beta-AR state. The total number of beta-AR in lymphocytes (beta-ARtotal) was inversely correlated with the VO2 max (r = -0. 368; P < 0.05) and the VO2@VT (r = -0.359; P < 0.05). Similar relationships were also observed between the number of beta-AR in cell surface and both VO2 max (r = -0.491; P < 0.05) and VO2@VT (r = -0.498; P < 0.05). However, no correlation was obtained between the number of beta-AR in intracellular compartments and either VO2 max or VO2@VT. The beta2-AR mRNA level quantified by the use of competitive reverse transcription-polymerase chain reaction was inversely correlated with VO2@VT (r = -0.567; P < 0.05) and positively correlated with beta-ARtotal (r = 0.521; P < 0.05). These findings suggest that the beta-AR number in lymphocytes is inversely correlated with aerobic capacity. This relationship may be explained by downregulation of beta-AR, including internalization with subsequent degradation of the receptors and inhibition of the beta-AR biosynthesis.

Adolescent↗

PubMed1998

Expression of B7-1, B7-2, and interleukin 12 in bleomycin-induced pneumopathy in mice.

BACKGROUND: The bleomycin-induced pneumopathy involves a T cell-mediated immune response. T cell activation requires both antigen/MHC recognition and costimulatory signals. The CD28 receptor on T cells with its ligand B7 represents one of the most important examples of this costimulation. Interleukin 12 (IL-12) has a strong synergistic effect with the B7-1/CD28 interaction on inducing proliferation and cytokine production in T cells. METHODS: In this study, we investigated the expression of B7-1, B7-2, and IL-12 in bleomycin-induced pneumopathy in mice using reverse transcription polymerase chain reaction (RT-PCR), RT in situ PCR, and immunohistochemistry. RESULTS: We observed concurrent upregulation of B7-1, B7-2, and IL-12p40 mRNA in the lung tissues at 1 h to 7 days after bleomycin instillation into the trachea. B7-1 mRNA and protein were found in bronchiolar epithelial cells as well as macrophages, B7-2 and IL-12p40 mRNA appeared to be expressed in mononuclear cells. CONCLUSIONS: These findings indicate that T cell-mediated immune response in this model involves the upregulation of B7-1, B7-2, and IL-12p40 mRNA, and also demonstrate the aberrant expression of B7-1 in bronchiolar epithelial cells.

Animals↗

PubMed1998

Endothelial cell apoptosis in lipopolysaccharide-induced lung injury in mice.

BACKGROUND: Studies have shown the importance of apoptosis in vascular injury in vitro. We postulated that apoptosis of the endothelium contributes to vascular injury in vivo and may be involved in acute lung injury. METHODS: To test this hypothesis, we investigated the incidence of endothelial cell apoptosis in acute lung injury induced in mice by the administration of lipopolysaccharide (LPS). Male ICR mice were administered LPS (20 mg/kg body weight) intravenously and sacrificed at specified times thereafter. RESULTS: Histologic findings were consistent with acute lung injury which increased with time from 3 to 48 h after injection. Electrophoretic analysis of DNA that was extracted from lung tissue and 3'-end-labeled with digoxigenin demonstrated a fragmentation of DNA starting at 6 h. In situ terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end-labeling (TUNEL) demonstrated DNA strand breaks in the endothelial cells. TUNEL also revealed DNA strand breaks in bronchial and alveolar epithelial cells as well as inflammatory cells in the interstitium. These TUNEL-positive cells appeared 6 h after injection. Electron-microscopic examination of the endothelium strongly suggested the morphological characteristics of apoptosis. CONCLUSION: Apoptosis was induced by LPS administration in endothelial cells in vivo. A role for such apoptosis is suggested in acute lung injury.

Animals↗

PubMed1998

Increased cardiac angiotensin II receptors in angiotensinogen-deficient mice.

Two subtypes of angiotensin II (Ang II) receptors, type 1 (AT1-R) and type 2 (AT2-R), have been identified in the heart. However, little is known about the regulation of cardiac AT1-R and AT2-R by Ang II in vivo. Thus, we examined cardiac AT1-R and AT2-R in angiotensinogen-deficient (Atg-/-) mice that are hypotensive and lack circulating Ang II. Cardiac Ang II receptors (Ang II-R) were assessed by radioligand binding with 125I-[Sar1,Ile8]-Ang II in plasma membrane fractions. AT1-R and AT2-R were distinguished using their specific antagonists CV-11974 and PD123319, respectively. Total densities of Ang II-R and AT1-R density were significantly greater in the Atg-/- mice than Atg+/+ mice (31.1+/-2.8 versus 18.8+/-2.1, 28.7+/-3.0 versus 16.9+/-2.3 fmol/mg protein, P<.01, respectively), and AT2-R showed a slight but not significant increase in Atg-/- mice relative to Atg+/+ control animals. Kd values were not different between the two groups. In contrast to binding experiments, levels of Ang II type 1a receptor (AT1a-R) and AT2-R mRNA did not differ between Atg-/- and Atg+/+ mice. These results suggest that lack of Ang II may upregulate AT1-R through translational and/or posttranslational mechanisms in Atg-/- mice.

Angiotensin II↗

PubMed1998

Effect of genetic deficiency of angiotensinogen on the renin-angiotensin system.

This study examined expression of renin-angiotensin system (RAS) component mRNAs in angiotensinogen gene knockout (Atg-/-) mice. Wild-type (Atg+/+) and Atg-/- mice were fed a normal-salt (0.3% NaCl) or high-salt (4% NaCl) diet for 2 weeks. Angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin II type la receptor (AT1A), and angiotensin II type 2 receptor (AT2) mRNA levels were measured by Northern blot analysis. In Atg+/+ mice, activities of circulating RAS and renal angiotensinogen mRNA level were decreased by salt loading, whereas levels of renal and cardiac ACE; renal, brain, and cardiac AT1A; and brain and cardiac AT2 mRNA were increased by salt loading. Although activities of circulating RAS were not detected in Atg-/- mice, salt loading increased blood pressure in Atg-/- mice. In Atg-/- mice, renal renin mRNA level was decreased by salt loading; in contrast, salt loading increased renal AT1A and cardiac AT2 mRNA levels in Atg-/- mice, and these activated levels in Atg-/- mice were higher than those in Atg+/+ mice fed the high-salt diet. Thus, expression of each component of the RAS is regulated in a tissue-specific manner that is distinct from other components of systemic and local RAS and that appears to be mediated by a mechanism other than changes in the circulating or tissue levels of angiotensin peptides.

Angiotensinogen↗

PubMed1998

Expression of p53, p21 (Waf1/Cip1/Sdi1) and Fas antigen in collagen vascular and granulomatous lung diseases.

Fas is expressed in various cells and transduces the cell death signal. p21 is a mediator of p53-dependent G1 arrest associated with deoxyribonucleic acid (DNA) damage. The upregulation of p53 and p21 associated with DNA damage in idiopathic pulmonary fibrosis has been described previously. In this study, p53, p21, and Fas expression and DNA damage were examined in interstitial pneumonia associated with collagen vascular diseases (CVD-IP). DNA damage was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL) and p53, p21 and Fas proteins were detected by immunohistochemistry in 13 cases of CVD-IP, 13 of sarcoidosis, seven of hypersensitivity pneumonitis (HP) and eight control patients with normal lung parenchyma. TUNEL-positive signals were found in bronchiolar or alveolar epithelial cells in 11 of 13 (85%) specimens of CVD-IP, but not in sarcoidosis, HP or controls, except for a case of chronic HP with pulmonary fibrosis. p53, p21 and Fas were detected in bronchiolar or alveolar epithelial cells in nine (69%), 10 (77%) and 12 (92%) of 13 specimens of CVD-IP, respectively, but not in sarcoidosis, HP or controls, except for a case of chronic HP. These results suggest that the upregulation of p53, p21 and Fas in bronchiolar and alveolar epithelial cells associated with deoxyribonucleic acid damage may participate in the process of pulmonary fibrosis in interstitial pneumonia associated with collagen vascular diseases and chronic hypersensitivity pneumonitis.

Adult↗