Über die „thermo-dilution“-Methode zur Bestimmung des Herzzeitvolumens am narkotisierten und unnarkotisierten Hund

Zusammenfassung 1. Vergleichende Messungen des Herzzeitvolumens mit der thermodilution-Methode, nach dem Fickschen Prinzip und mit dem Farbstoff-Verdünnungs-Verfahren zeigten gute Übereinstimmung und bewiesen die Brauchbarkeit der thermo-dilution-Methode.2. Die Versuche ergaben weiterhin, daß die Herzzeitvolumen-Bestimmung mit der thermo-dilution-Methode auch am unnarkotisierten Tier möglich ist.Mit 4 Textabbildungen     

In situ expression of β1, β3 and β4 integrin subunits in non-neoplastic endothelium and vascular tumours

Endothelial cells play an important role in adhesive interactions between circulating cells and extracellular matrix proteins. In vitro studies have shown that many of these processes are mediated by a superfamily of heterodimeric transmembrane glycoproteins called integrins. The distribution patterns of 1, 3 and 4 integrin subunits in endothelial cells (EC) in situ were examined immunohistochemically on serial forzen sections of a wide range of non-neoplastic tissues and of vascular tumours, both benign and malignant. Expression of the 1 subunit was a constitutive feature of EC. Among the 1-associated subunits, 5 and 6 were broadly distributed in EC, irrespective of vessel size and microenvironment. The 3 subunit displayed intermediate levels of expression with a slight preference for small vessel EC. Presence of 1 was confined to EC of capillaries and venules/small veins. Expression of 2 in EC was inconsistent. With rare exceptions, the 4 chain was absent in EC. The 3 and v subunits were expressed in most EC, though not always concomitantly. In contrast to the 1 chain, however, these integrin subunits were absent in EC of glomerular capillaries and were expressed variably in sinusoidal EC. The 4 chain was evenly present in the great majority of EC, except for those of large vessels. In vascular tumours, the patterns of 1 and 1 to 6 subunit expression generally corresponded to those found in their non-neoplastic counterparts. Expression of 3, v and 4 chains, however, decreased in neoplasia, especially in angiosarcomas. These data show that EC dispose of broad and at the same time differential repertoires of integrin subunits that presumably reflect vessel-type associated functional differences among these cells. In vascular tumours, the orthologous distribution patterns of 1 and 1 to 6 chains are conserved in most instances while the amounts of 3, v and 4 subunits expressed in EC tend to decrease in the course of malignant transformation.Dedicated to Prof. Dr. med. Dres. h.c. Wilhelm Doerr on the occasion of his 80th birthday     

Theβ−tubulin genes ofDrosophila auraria are arranged in a cluster

When the 1-, 2- and 3-tubulin-specific DNAs fromDrosophila melanogaster were used as probes to recognize tubulin-specific sequences in the chromosomes ofDrosophila auraria, they were found to hybridize to the same polytene band in region 32C of the 2L polytene chromosome. Three overlapping clones were isolated from a EMBL 3 genomic library ofD. auraria, and they all contain -tubulin-specific sequences based on hybridization and partial-sequencing experiments of subcloned fragments. These clones hybridize in situ to the same polytene chromosome band in region 32C and they represent an approximately 35-kb fragment of genomic DNA.     

Estradiol attenuation of beta-amyloid-induced toxicity: a comparison o.

17-estradiol (E2) has been shown to attenuate the toxicity of -amyloid peptides (A) in neuronal cultures with the effective concentration of E2 ranging from low nM to high M. This study compares the effective neuroprotective concentration of E2 against both A-mediated toxicity in a human neuroblastoma cell line, SK-N-SH using cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an endpoint to the effective E2 concentration obtained using a calcein acetoxymethyl ester (calcein AM) viability assay. The minimum E2 concentration required for protection varied 1000-fold between the two viability assays with 1 nM E2 conferring significant protection in the calcein AM assay but 1 M E2 required for significant protection in the MTT assay. Interestingly, the maximal inhibition of MTT reduction occured at sub-toxic A concentrations and did not correlate with other markers of cellular viability including calcein fluorescence, dye exclusion (propidium iodide or trypan blue), cellular ATP levels, or reduction of another tetrazolium dye, 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl) tetrazolium (MTS). By contrast, there was no difference between the MTT and calcein AM assays with respect to H₂O₂ toxicity or the neuroprotective effectiveness of 10 nM E2 against H_{2 2} toxicity. These results indicate that low concentrations of E2 can attenuate A and H₂O₂ toxicity in a human neuroblastoma cell line. Further, these results suggest that the MTT assay is not an appropriate assay for the determination of E2-mediated attenuation of A toxicity.     

Receptors and G proteins as primary components of transmembrane signal transduction

Seven-transmembrane receptors signal through nucleotide-binding proteins (G proteins) into the cell. G proteins are membrane-associated proteins composed of three subunits termed , and , of which the G subunit classifies the heterotrimer. So far, 23 different mammalian G subunits are known, which are grouped in four subfamilies (G_s, G_i, G_q, G₁₂) on the basis of their amino acid similarity. They carry an endogenous GTPase activity allowing reversible functional coupling between ligand-bound receptors and effectors such as enzymes and ion channels. In addition, five G and seven G subunits have been identified which form tightly associated heterodimers. Upon activation by a ligand-bound receptor the G protein dissociates into G and G, which both transmit signal by interacting with effectors. On the G protein level, specificity and selectivity of the incoming signal is accomplished by G protein trimers composed of distinct subunits. On the other hand, many receptors have been shown to activate different G proteins, thereby regulating diverse signal transduction pathways.Abbreviations CT Cholera toxin - PT Pertussis toxin     

Untersuchungen Mit J131-Markiertemβ-Globulin Zur Frage Der Abstammung Der Liquoreiweisskörper

Zusammenfassung Die Abstammung der-Globuline im Liquor wurde bei 20 Fällen mit den verschiedensten neurologischen Erkrankungen untersucht. — Die spezifische Aktivität der-Globuline war bei normalen und pathologischen Liquors ausnahmslos niedriger als im Serum. Es treten demnach nur einzelne Serum--Globuline in den Liquor über, ein verschieden großer Anteil der Liquor--Globuline wird im Liquorraum gebildet. Die-Fraktion im Liquor besitzt einen Serumanteil, von dem die liquoreigenen oder auch cerebrogenen-Globuline unterschieden werden können. Beziehungen zwischen der Höhe des liquoreigenen-Globulinanteils zu einzelnen Krankheitsgruppen waren nicht herzustellen. Es ließ sich aber zeigen, daß eine Erhöhung des elektrophoretisch ermittelten relativen-Globulingehaltes im Liquor bei pathologischen Fällen nicht — wie bisher angenommen wurde — mit einer Zunahme des cerebrogenen Eiweißes einherzugehen braucht. — Die Bedeutung des liquoreigenen-Globulins ist noch unbekannt, auch ist es nicht möglich zu entscheiden, welche einzelnen Proteine innerhalb der-Fraktion im Liquorraum entstanden sind oder aus dem Serum stammen.Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Myocardial β-adrenergic receptor signaling in vivo: insights from transgenic mice

Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor downregulation) and impaired receptor function (receptor uncoupling). These changes in the §-adrenergic receptor (§ AR) system may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G protein coupled -adrenergic receptors through the action of the second messenger cAMP. The -adrenergic receptors themselves are regulated by a set of specific kinases, termed the G protein-coupled receptor kinases. The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted (knock out) mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.Abbreviations -AR -Adrenergic receptor - GRK G protein coupled receptor kinase - LV Left ventricular     

Identification and quantitation of cortisol metabolites in rat liver homogenate and -slices

Summary Cortisol-1, 2-H³ was incubated with rat liver homogenate and/or rat liver slices in the presence of a NADPH-generating system. The following metabolites could be identified in adult male rats: -cortol, allo--cortol, 3-allo--cortol, 20-hydroxy-cortisol, 11, 17, 20, 21-tetrahydroxy-5-pregnan-3-one, 3-allotetrahydrocortisol, tetrahydrocortisol, trace amounts of allotetrahydrocortisol and two highly polar metabolites only partly identified. In female rats only tetrahydrocortisol, allotetrahydrocortisol and allodihydrocortisol could be detected in significant amounts.The radioactive metabolites mentioned above were localized and quantitated on paper chromatograms by a 4-radiochromatogram scanner. A nearly perfect correlation was found between these results so obtained and those given by liquid-scintillation counting of each metabolite after its elution from the paper.Part of this work was supported by grant n° 695 of the National Fonds voor Wetenschappelijk Geneeskundig Onderzoek.Stagiair of the Nationaal Fonds voor Wetenschappelijk Onderzoek.     

Comparison of abilities of recombinant interleukin-1α and -β and noninflammatory IL-1β fragment 163–171 to upregulate C3b receptors (CR1) on human neutrophils and to enhance their phagocytic capacity

Both recombinant IL-1 and - caused an upregulation of C3b receptors (CR1) on human neutrophils and caused a receptor-mediated enhancement of phagocytosis of C3b·IgG-coated microspheres by these leukocytes. The and forms of the recombinant cytokine were of comparable potency regarding CR1 upregulation, although both generally had less than 25% of the potency of FMLP in this respect. Recombinant IL-1 was slightly more potent than the form of the cytokine regarding phagocytosis of opsonized microspheres and, again, both forms were less potent than FMLP in causing an enhancement of phagocytosis by neutrophils. The synthetic noninflammatory immunostimulatory nonapeptide corresponding to residues 163–171 of IL-1 was completely inert with respect to upregulation of CR1 on neutrophils and the enhancement of phagocytosis by these cells. Thus this domain in the intact IL-1 molecule apparently is not involved in CR1 upregulation and the ensuing enhancement in phagocytosis by neutrophils, although it is apparently important in the immunostimulatory activity regarding the proliferation of lymphocytes.     

Cortico-cortical connections of two electrophysiologically identified arm representations in the mesial agranular frontal cortex

Summary Neuronal tracers (diamidino yellow or wheat germ agglutinin conjugated with horseradish peroxidase) were injected in the arm representations of area 6a (mesial surface, area F3), in the arm representation of area 6a (mesial surface) as well as in the eye field of area 6a (dorso-medial surface). The results showed that the arm representation of area F3 receives topographically organized afferents from motor and premotor areas (areas F1, F2, F4 and F5). A further connection was found with that part of cingulate cortex that sends projections to the spinal cord. In contrast, the arm representation of area 6a receives afferents chiefly from area F5, the prefrontal cortex and that part of cingulate sulcus which has few, if any, connections with the spinal cord. No connections were found with the precentral motor cortex (area F1). The area 6a eye field receives afferents mostly from the frontal eye field. Further connections are with the prefrontal cortex and cingulate gyrus. It is suggested that the so called low level motor functions of supplementary motor area are due to the activity of area F3, whereas the so called high level motor functions depend upon an independent area located in area 6a.     

Mapping thyrotropin β subunit gene in man and mouse

Thyrotropin (TSH) is composed of two subunits: and . Previously, we have mapped the TSH gene to human chromosome 6 and mouse chromosome 4. In this study we have located the human TSH gene on chromosome 1 and the mouse TSH gene to chromosome 3. These data suggest that the TSH gene lies in a conserved linkage group with the genes for amylase 1 and 2, nerve growth factor, and the protooncogene Nras.     

Trennung der intestinalen β-Galactosidasen beim lactose-toleranten Erwachsenen durch Ultrazentrifugation im Dichtegradienten

Zusammenfassung Die intestinalen-Galactosidasen von 4 lactose-toleranten, erwachsenen Mitteleuropäern wurden im Saugbiopsie-Gewebe nach Solubilisierung mit Triton X-100 in einem linearen Mannitol-Gradienten (5–20%) auf der Ultrazentrifuge bei 4°C und 44000 U/min getrennt. Bei 12stündiger Zentrifugation fanden sich 3 Fraktionen, von denen die beiden schneller sedimenticrenden Lactose spalten. Alle 3 Fraktionen hydrolysieren p-Nitrophenyl--Galactosid. Die 3 isolierten-Galactosidasen entsprechen wahrscheinlich der neutralen Bürstensaum-Lactase, der sauren lysosomalen Lactase und einer cytoplasmatischen Hetero--Galactosidase.     

Bradykinin B1 and B2 receptor agonists synergistically potentiate interleukin-1-induced prostaglandin biosynthesis in human gingival fibroblasts

The interactions between bradykinin (BK) and interleukin-1 (IL-1) on prostaglandin formation in human gingival fibroblasts have been studied. IL-1 and IL-1 stimulated prostaglandin E₂ (PGE₂) formation in the gingival fibroblasts with IL-1 being the most potent agonist. The effects of both IL-1 and IL-1 on PGE₂ biosynthesis was synergistically potentiated by BK, in a dose-related manner. The synergistic interaction between IL-1 and BK on PGE₂ production was seen both with B1 (des-Arg⁹-BK) and B2 (BK, Lys-BK) BK receptor agonists. No synergistic interaction between BK and IL-1 was seen on arachidonic acid release. These data suggest that BK and IL-1 act in concert to enhance prostanoid formation in inflammatory lesions and that the level of interaction is distal to phospholipase activity.     

Modulation of hematopoietic colony formation of stem cells in peripheral blood by anti-TGF-β in patients with severe immunosuppression

Summary The influence of transforming growth factor- (TGF-) on hematopoiesis has been evaluated by adding blocking antibodies against TGF- to colony forming assays (CFU-c). When optimum concentrations of recombinant growth factors, granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukin-3 (IL-3) were added to stem cells from the peripheral blood of healthy individuals and certain patients with tumors or HIV infection, the anti-TGF- capable of blocking 5 ng/ml of active TGF- had no significant influence on erythroid or myeloid colony formation. However, in certain immunosuppressed individuals, anti-TGF- resulted in a significant decrease of erythroid colony formation and slight suppression of myeloid colony formation. The significant inhibition of hematopoiesis by plasma of HIV patients could be due to the presence of active forms of TGF-. The results of the blocking experiments are consistent with the concept that TGF- in low concentrations is essential for erythropoiesis and myelopoiesis but that higher levels of TGF- primarily inhibit erythropoiesis in vitro. TGF- serves as a coordinating factor when efficient recruitment of granulocytes and monocytes is more essential than erythropoiesis and stem cell growth.Abbreviations BFU-E burst forming unit-erythroid - CFC colony forming cells - CFU-GEMM colony forming unit-granulocyte/erythroid/macrophage/megacaryocyte - CFU-GM colony forming unit-granulocyte/macrophage - EPO erythropoietin - GM-CSF granulocyte/macrophage-colony stimulating factor - HIV human immunodeficiency virus - IL-1 interleukin-1 - IL-3 interleukin-3 - IMDM Iscove's Modified Dulbecco's medium - PBS phosphate buffered saline - TGF- transforming growth factor- - TNF- tumor necrosis factor-     

Activity of beta-lactamase inhibitor combinations onEscherichia coli isolates exhibiting various patterns of resistance to beta-lactam agents

The efficacy of the clinically available -lactam/-lactamase inhibitor combinations (amoxicillin/clavulanic acid (CA), ticarcillin/CA, amoxicillin/sulbactam, and piperacillin/ tazobactam) was evaluated on 300 amoxicillin-resistantEscherichia coli isolates having the main patterns of -lactam resistance. The patterns, which reflect the production of various -lactamase enzymes, were analyzed by a principal component analysis of susceptibility to 11 -lactam antibiotics or -lactam/-lactamase inhibitor combinations. Sixty-two percent of strains were not very susceptible to penicillins, cephalothin, or any -lactam/-lactamase inhibitor combinations except for piperacillin/tazobactam; these strains may represent high-level broad-spectrum -lactamase (so-called penicillinase) production phenotype or inhibitor-resistant TEM-like enzyme production phenotype. Of the strains, 14.7 % were resistant to amoxicillin and ticarcillin compatible with low-level broad-spectrum -lactamase production phenotype; 5.7 % were cefoxitin resistant and were postulated to present a high-level cephalosporinase production phenotype; and 2.6 % were resistant to cephalothin only, attributable to a low-level cephalosporinase production phenotype. Three percent of strains were intermediate or resistant to cefotaxime and may produce an extended-spectrum -lactamase, and the remaining strains (12 %), resistant to all tested antibiotics except for cefotaxime and piperacillin/tazobactam, were hypothesized to produce both broad-spectrum -lactamase plus cephalosporinase. The minimal inhibitory concentration (MIC) for these phenotype patterns indicated that combinations of CA plus amoxicillin or ticarcillin, or sulbactam plus amoxicillin, restored the activity of penicillins against phenotype 1 strains, whereas these combinations remained inactive against the other phenotype strains. Piperacillin plus tazobactam showed the best in vitro effect against the strains of all resistance phenotypes.     

Immunohistochemical studies of human FSH producing pituitary adenomas

Summary Ten FSH producing pituitary adenomas were studied immunohistochemically. 9 cases were in males, and 7 showed elevated serum FSH levels. Immunohistochemically, all cases showed the presence of -subunit and FSH- subunits in many tumour cells. These two subunits were frequently colocalized in the same cells. However, the expression of LH- subunit was extremely low (1 of 10 cases exhibiting occasional LH- positive tumour cells), although it has been reported that FSH- and LH- subunits are colocalized in the same cells of the normal adult pituitary gland. Immunoelectron microscopically, -subunits and FSH- were present in the secretory granules and suggested the co-release of subunits or secretion of combined form of FSH. In 7 cases, TSH- was positive, and in some cases, TSH- was colocalized in the same tumour cells which contained -subunit and FSH- subunit. A few cases also demonstrated immunoreactivity for PRL and ACTH. Our immunohistochemical studies suggest that FSH adenomas are multihormonal and that there is abnormal gene expression in FSH cells with loss of LH- appearance and co-expression of TSH-.     

Expression of growth factor receptors in injured nervous tissue. I. Axotomy leads to a shift in the cellular distribution of specific beta-nerve growth factor binding in the injured and regenerating PNS

Summary We have studied -nerve growth factor (-NGF) receptor expression in the injured and regenerating chick PNS using [¹²⁵I]-iodinated -NGF as a radioactive probe to map and quantitate autoradiographically thein situ distribution of specific [¹²⁵I] -NGF binding.Two different mechanisms are involved in the reappearance of specific [¹²⁵I] -NGF binding on the normally unlabelled adult peripheral nerves. The anterograde and retrograde axonal transport of -NGF binding sites leads to a rapid but transient accumulation of [¹²⁵I] -NGF binding on both sides of crushed or transected sciatic and brachial nerves. There is a dramatic decrease in the axonal transport of -NGF binding sites, starting 1 day after, nerve injury (1 DPO) and reaching basal levels of 10–20% of the control values at 3 to 10 DPO. Gradual but complete recovery of this axonal transport was noted in the sciatic neurites allowed to regain contact with their peripheral targets. A very different regulation pattern was observed for the local reappearance of specific [¹²⁵I] -NGF binding on the endoneurial Schwann cells throughout the distal part of the axotomized nerve. It was first observed at 4 DPO, becoming maximal at 6 DPO. Reinnervation of the nerve after crush led to a rapid decrease of this specific [¹²⁵I] -NGF binding, which followed a proximo-distal temporal gradient.These results show that axotomy leads to a drastic decrease in the axonal expression of [¹²⁵I] -NGF binding, while causing its appearance on the Schwann cells of the denervated endoneurium. They suggest that these endoneurial cells may become the primary target for -NGF following axotomy and during regeneration.     

Sublocalization on chromosome 21 of human interferon-alpha receptor gene and the gene for an interferon-gamma response protein

The cellular responses to alpha and beta interferons (IFN- and -) are mediated through the IFN-/ (type I) receptor, while the response to IFN- is mediated through the IFN- (type II) receptor. The receptors for IFN-/ and IFN- are encoded by genes on human chromosomes 21 and 6q, respectively. The presence of chromosome 21q confers both ligand binding and responsiveness to human IFN-/, whereas chromosome 6q confers binding of Hu-IFN-, but not cellular responsiveness on somatic cell hybrids. Chromosome 6q (i.e., the Hu-IFN- receptor gene) and chromosome 21q are both necessary for the cellular response of somatic cell hybrids (from fibroblasts) to Hu-IFN-. It is conceivable that the factor mediating activity through the IFN- receptor is, in fact, the IFN- receptor, or that the two genes are distinct but part of an interferon response region. Here we more precisely localize on human chromosome 21 the genes for the IFN- receptor and for the factor(s) mediating the action of IFN- through the chromosome 6-encoded receptor. Hamster-human somatic cell hybrids containing various fragments of human chromosome 21 were used. The presence of the human IFN-/ receptor was determined by binding³²P-labeled human IFN- to cells, covalently cross-linking the [³²P]IFN--receptor complex, and analyzing it by SDS-polyacrylamide gel electrophoresis. The presence of the IFN- receptor-related factor mediating cellular responsiveness was determined by HLA induction in hybrid cells containing the IFN- receptor (chromosome 6q), a transfected copy of the human HLA-B7 gene, and various portions of chromosome 21. In all hybrids examined, the two genes cosegregate. Specifically, both genes are localized to the region of chromosome 21 containing the markers D21S58, D21S65, and GART and appear to be proximal to D21S58. The implications for IFN action are discussed.     

Selection and properties ofPseudomonas aeruginosa variants resistant to beta-lactam antibiotics

The relation between basal and inducible-lactamase production and resistance to-lactam compounds was studied in five clinicalPseudomonas aemginosa isolates and their corresponding resistant variants selected in the presence of either piperacillin, ceftazidime or aztreonam. In all wild-type strains enzyme levels were barely detectable in the uninduced state and most-lactams, including sulbactam and clavulanic acid, exhibited poor induction potency. Imipenem proved to be the most potent inducer in both these strains and their resistant variants. In the variants selected by either piperacillin or ceftazidime enzyme production amounted to 1.28 units/mg protein of the cell-free supernatants following the addition of-lactams as inducers. Additionally, these variants exhibited the phenomenon of non-specific induction, i.e. the increase of enzyme production by either a complex nutrient medium or by addition of vitamins. Enzyme production in the aztreonam-resistant variants was identical to that in the wild-type strains with a single exception, where the entire derepression of-lactamase production in one of the variants took place. Derepression of the chromosomally mediated enzyme affects the susceptibility to ureidopenicillins more than that to carboxy-penicillins and cephalosporins, whereas the-lactamase-independent resistance results in increased resistance to all-lactams with the single exception of imipenem.     

Glucocorticoids and TGF-β1 Synergize in Augmenting Fibroblast Mediated Contraction of Collagen Gels

TGF- plays a central role in the initiation and progression of pulmonary fibrosis. Glucocorticoids are frequently used to treat fibrotic diseases, but beneficial effects are often modest. Both TGF- and glucocorticoids have been reported to increase fibroblast contraction of native collagen gels, a model of fibrotic tissue remodeling. Therefore, we sought to determine how glucocorticoids interact with TGF- in this system. In this study, human fetal lung fibroblasts (HFL-1) were pretreated with or without TGF- for 72 h before they were cast into type I collagen gels. Various concentrations of glucocorticoids (budesonide or hydrocortisone) were added at the time of casting. Gel size was then monitored at different times after gel release. The surrounding media were collected for the assay of prostaglandin E₂ (PGE₂) and the cell lysates were analyzed for cyclooxygenase (COX) expression by immunoblot. Glucocorticoids alone significantly enhanced fibroblast-mediated contraction of collagen gels (P < 0.01) and dose-dependently inhibited PGE₂ release by HFL-1 fibroblasts. TGF- significantly augmented gel contraction but also induced a 30% increase in PGE₂ release and increased the expression of COX-1. Glucocorticoids inhibited TGF-1 induced-PGE₂ release, and enhanced TGF- augmented gel contraction without significantly affecting TGF- augmented COX-1 expression. Indomethacin, a COX inhibitor, increased TGF- augmented gel contraction but had no further effect when added together with glucocorticoids. Thus, glucocorticoids can synergize with TGF- in augmenting fibroblast mediated collagen gel contraction through the inhibition of PGE₂ production. Such interactions between glucocorticoids and TGF- may account, in part, for the lack of response of fibrotic diseases to glucocorticoids.