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Biomedical subjects

J M Dayer

Publications and source records attributed to J M Dayer.

At least 55 records · Page 3Linked to original sources
PubMed1998

Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: different sensitivity to inhibition between systemic sclerosis and control fibroblasts.

OBJECTIVE: To assess the role of T lymphocyte-fibroblast contact in type I collagen production by cultured dermal fibroblasts from normal individuals and from patients with diffuse systemic sclerosis (SSc). METHODS: Cell membranes were prepared from activated CD4+ and CD8+ T cells, or type 1 T helper (Th1) clones, and added to confluent fibroblast monolayers. Type I collagen production was measured in culture supernatants, and messenger RNA (mRNA) levels of type I procollagen alpha1 (pro alpha1[I]) and matrix metalloproteinase 1 (MMP-1) were evaluated by Northern hybridization analysis. RESULTS: Dose-dependent inhibition of type I collagen production was observed with CD4+ and CD8+ T cells from both SSc patients and controls. Inhibition of type I collagen was significantly less pronounced in fibroblasts from SSc patients than in fibroblasts from controls (P < 0.02). Inhibition was not reversed by the addition of exogenous transforming growth factor beta, interleukin-4, interleukin-1 receptor antagonist, anti-tumor necrosis factor, anti-CD40, or indomethacin, whereas anti-interferon-gamma (IFNgamma) reversed Th1-mediated inhibition. This inhibitory activity was specific for type I collagen, since mRNA levels of pro alpha1(I) were decreased, whereas mRNA levels of MMP-1 were strongly increased. CONCLUSION: The production of type I collagen by skin fibroblasts is specifically down-regulated by membranes from activated T cells. The contact-dependent regulatory activity exerted by T cells on fibroblasts depends, at least in part, on the presence of membrane-associated IFNgamma. However, SSc fibroblasts are more resistant to inhibition than are fibroblasts from normal individuals.

Aged↗
PubMed1998

Inflammation: "a natural experiment" for the systemic pathogenicity of cytokines.

It has previously been demonstrated that the overproduction of interleukin-6 (IL-6) is a key element in the clinical and biological abnormalities encountered in Castleman's disease (CD). The particular case of a male child with a localized form of CD is reported. In this patient, evidence was found of a correlation between systemic manifestations and circulating IL-6, and IL-6 gene overexpression in the germinal centers of hyperplastic lymph nodes. Circulating IL-6 levels were 10- to 100-fold higher than in all CD cases previously documented. This unique biological feature was closely associated with high levels of circulating IL-1 and tumor necrosis factor-alpha (TNF-alpha), which are known for their ability to induce and/or amplify IL-6 production. One month after surgical removal of the pathological lymph node, the clinical and biological abnormalities diminished, while circulating IL-6 levels dropped dramatically eight months later. It is worth noting that after resection, the time-course of the IL-6 decrease closely correlated with that of IL-1 and TNF-alpha. Considering that in various inflammatory diseases IL-1, TNF-alpha and IL-6 may act in a synergistic manner in inducing systemic manifestations, this case report raises new questions as to the nature of the systemic pathogenicity of cytokines in CD.

Castleman Disease↗
PubMed1998

Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and the tissue-inhibitor of metalloproteinases-1 over that of interleukin-1beta and metalloproteinases.

On direct cell-cell contact, stimulated T lymphocytes potently trigger the production of pro-inflammatory factors such as interleukin-1beta (IL-1beta) and matrix metalloproteinases (MMP-1 and MMP-9), as well as anti-inflammatory factors such as IL-1 receptor antagonist (IL-1Ra) and the tissue inhibitor of metalloproteinases (TIMP-1) in peripheral blood monocytes and the monocytic cell line THP-1. Such mechanisms might play an important part in many inflammatory diseases where tissue destruction occurs. To assess whether anti-inflammatory agents such as dexamethasone (DEX) and leflunomide (LF) would affect contact-activation of monocytic cells, T lymphocytes were stimulated by PMA and PHA in the presence or absence of increasing concentrations of drug. LF and DEX (10- 4 M) inhibited the ability of stimulated T lymphocytes to activate monocytic cells by 66-97% and 43-70%, respectively, depending on the readout product. Upon contact with T lymphocytes stimulated in the presence of 10- 5 M LF, the molar ratio of IL-1Ra/IL-1beta and TIMP-1/MMP-1 produced by THP-1 cells was enhanced 3.6- and 1.9-fold, respectively, whereas it was enhanced only 1.3- and 1.4-fold upon contact with T lymphocytes stimulated in the presence of 10- 4 M DEX. Therefore, LF tends to favor the inhibition of pro-inflammatory and matrix-destructive factors over that of anti-inflammatory factors and metalloproteinase inhibitors, thus interfering with both inflammation and tissue destruction. These experiments indicate that LF and DEX have the potential to affect the capacity of stimulated T lymphocytes to activate, on direct cell-cell contact, monocytic cells. Furthermore, flow cytometric analysis revealed that surface molecules of T lymphocytes that were partially involved in contact-signaling of monocytes (i.e., CD69 and CD11) were not modulated by either LF or DEX, suggesting that factors which remain to be identified were mainly involved in the activation of monocytes on direct cell-cell contact.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Human Th1 cells preferentially induce interleukin (IL)-1beta while Th2 cells induce IL-1 receptor antagonist production upon cell/cell contact with monocytes.

The role of human T cells in the induction and regulation, upon cell/cell contact, of inflammatory responses by monocytic cells was investigated. The production of interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1Ra) by the monocytic THP-1 cell line was measured upon contact with either Th1 or Th2 cell clones. CD4+ T cell clones specific for purified protein derivative of Mycobacterium tuberculosis, predominantly Th1 [high interferon (IFN)-gamma and low IL-4 producers], or tetanus toxoid, predominantly Th2 (low IFN-gamma and high IL-4 producers), were generated. Cell membranes from antigen-stimulated, but not from resting T cell clones induced dose-dependent cytokine production by THP-1 cells. Th1 clones induced higher levels of IL-1beta production (484-806 pg/ml) than did Th2 clones (21-114 pg/ml). In contrast, Th1 clones induced lower levels of IL-IRa (0.9-7.8 ng/ml) than did Th2 clones (7.0-49.6 ng/ml). Similar results were obtained when T cell clones were activated by cross-linked CD3 and CD28. IL-1beta production by THP-1 cells correlated with IFN-gamma production by T cell clones but was unaffected by IFN-gamma neutralization. IL-1Ra production by THP-1 cells correlated with IL-4 production by T cells and was partially inhibited by IL-4 neutralization. These data indicate that activated Th1 and Th2 cells express different molecules on the cell surface able to induce distinct pro-inflammatory (IL-1beta) or anti-inflammatory (IL-1Ra) responses in monocytes. This differential induction of molecules with opposite effects on inflammation stresses the functional heterogeneity in CD4+ T cells.

CD28 Antigens↗
PubMed1997

Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria.

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.

Animals↗
PubMed1997

Direct contact with stimulated T cells induces the expression of IL-1beta and IL-1 receptor antagonist in human monocytes. Involvement of serine/threonine phosphatases in differential regulation.

Imbalance in the production of cytokines and their inhibitors plays a part in inflammation in chronic destructive diseases. Direct cell-cell contact with stimulated T cells markedly induces the production of pro-inflammatory cytokines and matrix metalloproteinases in monocytes. This study demonstrates that direct contact with stimulated T cells favours the production of IL-1beta over that of IL-1 receptor antagonist (IL-1Ra) in both peripheral blood monocytes and the monocytic cell line THP-1. In contrast, soluble factors secreted by stimulated T cells favour the production of IL-1Ra. Differentiation of THP-1 cells with 1,25-(OH)2D3 did not affect the balance between IL-1beta and IL-1Ra production, enhancing both cytokines 2.3- and 1.6-fold, respectively. Among different inhibitors of phosphorylation and dephosphorylation processes, only okadaic acid, an inhibitor of serine/threonine phosphatases, differentially modulates the production of IL-1beta and IL-1Ra. Indeed, okadaic acid upregulated IL-1beta and decreased IL-1Ra at the mRNA and protein level in monocytic cells activated by membranes of stimulated T cells. These results suggest that serine/threonine phosphatases play a part in the differential regulation of the production of IL-1beta and IL-1Ra by monocytes upon direct cell-cell contact with stimulated T cells. This mechanism may regulate the balance between the pro-inflammatory cytokine and its inhibitor, which balance dictates in part the outcome of the inflammatory process.

Cell Line↗
PubMed1997

Modulation of soluble and membrane-bound TNF-induced phenotypic and functional changes of human brain microvascular endothelial cells by recombinant TNF binding protein I.

In this study, the effects of TNF binding protein I (TBP I) on TNF-induced changes of human brain microvascular endothelial cells (MVEC) were investigated. TBP I completely abolished TNF-induced IL-6 production and E-selectin induction, while it partially inhibited TNF-induced IL-8 production and up-regulation of ICAM-1 and VCAM-1. Moreover, TBP I significantly inhibited TNF-induced cytotoxicity and leukocyte adherence on human brain MVEC. The inhibitory activity of TBP I for TNF was dose-dependent and related to the time of administration after TNF stimulation. In addition, TBP I inhibited membrane-bound TNF induced activation of human brain MVEC, but the concentration required was about 10-fold higher than that for soluble TNF. These results indicate a therapeutic potential for TBP I in diseases of the central nervous system associated with TNF overproduction.

Brain↗
PubMed1997

The IL-1 system in HIV infection: peripheral concentrations of IL-1beta, IL-1 receptor antagonist and soluble IL-1 receptor type II.

The proinflammatory cytokine IL-1beta is thought to be involved in ongoing HIV disease. Furthermore, its naturally occurring inhibitors soluble IL-1 receptor type II (sIL-1RII) and IL-1 receptor antagonist (IL-1Ra) may play a pivotal role in regulating its biological action. To investigate the involvement of the IL-1 system we determined serum levels of IL-1beta, IL-1Ra and sIL-1RII in 90 HIV- patients. The obtained values were compared with markers of disease progression such as CD4+ count, 5'-neopterin. Beta2-microglobulin and soluble tumour necrosis factor receptors (sTNF-R) p55 and p75 and then compared with C-reactive protein (CRP), granulocyte count, IL-6 and TNF-alpha. While IL-1Ra concentrations increased significantly with progressive CDC disease stages, sIL-1RII and IL-1beta were not altered in our cohort. IL-1Ra showed statistical relation to decreasing CD4+ lymphocytes and increasing 5'-neopterin, beta2-microglobulin, sTNF-R p55, sTNF-R p75. Furthermore, IL-1Ra correlated positively with serum IL-6, TNF-alpha, CRP and granulocytes. In contrast, sIL-1RII and IL-1beta tended to show an inverse correlation or showed no significant relationship to all these parameters. IL-1beta was measurable only in a limited number of samples. IL-1Ra showed a clear relationship to acute inflammatory events as well as to the different disease stages. Our data suggest a dissociation between IL-1Ra and sIL-1RII serum levels which may indicate that the two IL-1 binding proteins have different pathophysiological roles in HIV infection.

Adult↗
PubMed1997

Low levels of interleukin-1 receptor antagonist coincide with kidney involvement in systemic lupus erythematosus.

The objective was to study the relationship between the levels of interleukin-1 receptor antagonist (IL-1Ra) and disease activity and the acute-phase response in SLE patients with and without renal involvement. Twenty SLE patients who had distinct active clinical manifestations (eight glomerulonephritis, four systemic vasculitis without kidney involvement, nine skin rash, 12 arthritis, five serositis, four neuropsychiatric manifestations, three thrombocytopenia, one myositis and one haemolytic anaemia) were studied during a period of 8-12 months. Serum and plasma samples were taken at intervals of 6 weeks-4 months and tested for IL-1Ra, IL-1 beta, IL-6, IgG and anti-dsDNA, Clq, C3, C4 and C-reactive protein (CRP). IL-1Ra serum concentrations were increased in most SLE patients with active disease when compared to normal blood donors. However, at the time of flare, significantly higher levels of IL-1Ra were observed in patients with extra-renal disease as compared to other patients (median [range]: 363 [202-3041] and 4847 [268-27180] pg/ml for patients with and without renal involvement, respectively). This difference was not due to proteinuria. IL-1Ra levels did not correlate with SLEDAI score during flares, but they were elevated during flares in patients with extra-renal manifestations. When disease activity was at its highest, IL-1Ra concentrations correlated with IL-1 beta (r = 0.76; P < 0.001), IL-6 (r = 0.60; P < 0.01) and CRP (r = 0.61; P < 0.01), but not with C1q, C3, C4 and anti-dsDNA levels. The study showed that the pattern of inflammatory cytokines in active SLE varies in a manner that is dependent on which organs are involved. A relative absence of IL-1Ra response appears to be a feature characteristic of kidney involvement. IL-1Ra elevation clearly correlates with flares involving other organs.

Acute-Phase Reaction↗
PubMed1997

Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies.

Interstitial lung disease (ILD) is a complication of polymyositis (PM) and dermatomyositis (DM). It often manifests itself in association with myositis-specific antisynthetase autoantibodies, among which anti-Jo-1 antibodies are the most commonly encountered. In contrast, ILD associated with anti-Jo-1 antibodies without muscle involvement is rare and not well characterized. We report four patients presenting with ILD associated with anti-Jo-1 antibodies. Histological findings of transbronchial biopsies disclosed a pattern consistent with nonspecific interstitial pneumonitis, a CD8+ lymphocytosis was found in bronchoalveolar lavage. Only one of these patients developed an "antisynthetase syndrome" with PM, after nearly 2 yrs of severe ILD. The clinical conditions of all four cases showed stabilization or improvement when cyclosporine was added to their immunosuppressive treatment. These cases confirm that a CD8+ lymphocytic interstitial lung disease may be the first, and sole manifestation of autoimmune disease associated with anti-Jo-1 antibodies. Furthermore, they suggest that this form of interstitial lung disease apparently has a poor response to steroids and cytotoxic drugs, but may respond to moderate doses of cyclosporine and azathioprine in addition to low doses of steroids.

Aged↗
PubMed1997

Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity.

OBJECTIVE: To investigate the difference in acute phase protein responses between patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and spondyloarthropathies (SpA). METHODS: Circulating levels of cytokines inducing the production of acute phase proteins such as interleukin (IL)-6, IL-1 beta, and tumor necrosis factor (TNF)-alpha, and of cytokine inhibitors such as TNF soluble receptors (TNF-sR55 and TNF-sR75) and IL-1 receptor antagonist (IL-1ra), were measured in 2 cohorts of patients. The first cohort included 52 patients with SLE and 22 with RA, and the second included 21 with SLE, 20 with RA, and 18 with SpA. An examination at the time of blood collection and the Systemic Lupus Activity Measure (SLAM) index were used to assess disease activity in patients with SLE. Serum levels of IL-6 were measured using a biological assay, and concentrations of IL-1 beta, TNF-alpha, TNF-sR55, TNF-sR75, and IL-1ra were assessed by immunoassays. RESULTS: Although C-reactive protein (CRP) levels were significantly lower in SLE than in RA or SpA, the concentrations of circulating IL-6 or TNF-alpha were higher in SLE. The most striking observation was that TNF-sR levels were significantly higher in SLE than in RA or SpA. The TNF-alpha: TNF-sR ratio was also significantly lower in SLE than in RA. TNF-sR55 and TNF-sR75 levels correlated with disease activity in SLE. CONCLUSION: The weak acute phase protein response in SLE may be explained by a decreased ratio between inducing cytokines and their inhibitors. In addition, TNF-sR may prove a useful biological marker for the followup of SLE, where acute phase protein response is generally low during disease exacerbations.

Acute-Phase Proteins↗
PubMed1997

Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid.

OBJECTIVE: To determine levels of soluble interleukin 6 receptor-alpha (sIL-6R alpha) in synovial fluid (SF) and serum from patients with different rheumatic diseases, and to analyze its cellular origin compared to IL-6. METHODS: IL-6 and sIL-6R alpha concentrations were measured in sera, SF, and culture supernatants of different cells types using specific sandwich ELISA. RESULTS: IL-6 levels were significantly higher (30 to 1000-fold) in SF than in sera, and higher in inflammatory arthropathies such as rheumatoid arthritis (RA), chondrocalcinosis, and gout than in osteoarthritis (OA). sIL-6R alpha levels in SF from patients with RA, gout, and chondrocalcinosis were also higher (24.7 +/- 7.5, 23.2 +/- 9.1, and 19.5 +/- 7.4 ng/ml, respectively) than in patients with OA (10.1 +/- 5 ng/ml), although the difference was distinctly smaller. In contrast, sIL-6R alpha concentrations did not differ significantly between the sera of healthy donors and patients. sIL-6R alpha levels were similar in SF and sera from inflammatory arthropathies, but lower in all osteoarthritic SF, compared to their corresponding serum. In contrast to IL-6, sIL-6R alpha was produced in high amounts by hepatocytes but not by structural cells of the joint (chondrocytes, synoviocytes, fibroblasts, and endothelial cells). Polymorphonuclear cells and mononuclear cells released intermediate levels. A significant correlation between sIL-6R alpha concentration and total number of leukocytes was observed in SF. CONCLUSION: Elevated levels of sIL-6R alpha were found in serum, likely to result from a marked release by hepatocytes in vitro. That levels are higher in inflammatory SF may be due in part to release by inflammatory cells in situ.

Antigens, CD↗
PubMed1997

Interferon-beta not only inhibits interleukin-1beta and tumor necrosis factor-alpha but stimulates interleukin-1 receptor antagonist production in human peripheral blood mononuclear cells.

Imbalance between pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) and their respective inhibitors is likely to be involved in the pathogenesis of chronic inflammatory disorders such as multiple sclerosis and rheumatoid arthritis. Increasing evidence suggests that the administration of interferon-beta (IFN-beta) displays some efficacy in the treatment of patients with relapsing-remitting multiple sclerosis. The aim of the present study was to determine the effect of IFN-beta on the production of pro-inflammatory cytokines and their inhibitors by stimulated peripheral blood mononuclear cells (PBMC). IFN-beta decreased the production of both IL-1beta and TNF-alpha in a dose-dependent manner, by up to 80% and 55%, respectively. Simultaneously, IFN-beta increased the production of IL-1 receptor antagonist (IL-1Ra) by 37% and did not modulate the release of TNF-soluble receptors (TNF-sRs) p55 and p75. Therefore, by favoring the production of cytokine antagonists over that of pro-inflammatory cytokines, IFN-beta induces an imbalance supporting anti-inflammatory processes. This effect might account for some of the therapeutic benefit of IFN-beta.

Humans↗
PubMed1996

Expression and cleavage of tumor necrosis factor-alpha and tumor necrosis factor receptors by human monocytic cell lines upon direct contact with stimulated T cells.

Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine in inflammatory processes. A variety of mechanisms that modulate its activity have been described, one being its binding to soluble receptors (sTNFR). In this study, we demonstrate that human monocytic cells such as THP-1 respond to direct contact with a membrane preparation of stimulated HUT-78 cells by producing TNF-alpha and by releasing sTNFR-p75, but not sTNFR-p55, with different kinetics. TNF-alpha concentration peaked after 12 h of contact and then decreased, whereas sTNFR-p75 production increased progressively upon cell/cell contact. The decrease in TNF-alpha concentration is not due to trapping of TNF-alpha by its soluble receptors or other soluble or cell-associated molecules, but rather to a proteolytic activity associated to THP-1 cells. On the other hand, the increase in sTNFR-p75 release does not result from an increase in the cleavage of pre-existing cell-associated sTNFR-p75 but from an increase in TNFR-p75 expression, immediately followed by the cleavage of its extracellular domain. Phenylmethylsulfonylfluoride, a serine protease inhibitor, has a negative effect on both TNF-alpha degradation and sTNFR-p75 release by THP-1 cells. Thus, there may be an enzymatic activity associated to THP-1 cells that plays an important role in the neutralization of TNF-alpha activity both by degrading the molecule and by cleaving its receptors at the cell surface.

Cell Membrane↗
PubMed1996

Direct cell/cell contact with stimulated T lymphocytes induces the expression of cell adhesion molecules and cytokines by human brain microvascular endothelial cells.

Upon inflammation, stimulated, but not resting T lymphocytes cross the blood-brain barrier and migrate into the central nervous system. This study shows that direct contact between stimulated T lymphocytes and human brain microvascular endothelial cells (HB-MVEC) induces phenotypic and functional changes on the latter cells. Plasma membranes isolated from stimulated T lymphocytes (S-PM) up-regulated the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on isolated HB-MVEC. In addition, HB-MVEC activated by S-PM secreted interleukin (IL)-6 and IL-8. The levels of ICAM-1, E-selectin, IL-6, and IL-8 expressed in S-PM-activated HB-MVEC were similar to those observed with 1000 U/ml tumor necrosis factor (TNF). In contrast, VCAM-1 expression was 15% of that induced by TNF. Inhibitors of TNF diminished (< or = 45%), but did not abolish the expression of cell adhesion molecules and IL-6 induced by S-PM, IL-8 production being insignificantly affected (< or = 10%). This suggests that membrane-associated TNF was partially involved in HB-MVEC activation. The present study demonstrates that stimulated T lymphocytes are able to activate HB-MVEC upon direct cell contact. This novel mechanism of inducing the expression of cell adhesion molecules may prompt the initial adhesion of stimulated T lymphocytes to brain endothelium.

Brain↗
PubMed1996

Matrix metalloproteinases and TIMP in acute respiratory distress syndrome.

To investigate the implication of extracellular matrix proteinases in acute respiratory distress syndrome (ARDS), we determined 92 kD gelatinase (92 G'ase) and its natural antagonist, the tissue inhibitor of metalloproteinases-1 (TIMP) in bronchoalveolar lavage fluid (BALF) and plasma of 33 intensive care unit (ICU) patients presenting with trauma or septic shock. Eleven of these patients developed short-course ARDS, nine developed prolonged ARDS, and 13 did not progress to ARDS. Ten non-ICU patients served as controls. During the early phase of disease, 92 G'ase in BALF of ICU patients was higher than in controls, but plasma levels were not different. TIMP was increased in BALF and plasma in ARDS as compared with those of patients at risk. The 92 G'ase/TIMP ratio in BALF remained elevated in late phases of prolonged ARDS. The high intrapulmonary levels of 92 G'ase in patients at risk and with ARDS may reflect increased turnover of extracellular matrix in acute lung injury. Increased TIMP may interfere with tissue repair and fibrosis by its inhibition of 92 G'ase. Interleukin-6 (IL-6) could be involved in enhanced local synthesis of TIMP. The balance between 92 G'ase and TIMP may play an important role in lung remodeling, which is characteristic of ARDS.

Adult↗