Biomedical subjects

Martin Kolb

Publications and source records attributed to Martin Kolb.

16 recordsLinked to original sources

PubMed2006

Gene therapy for pulmonary diseases.

Gene therapy has not yet met the high expectations of "the early days." However, it is a promising new treatment for lung diseases. Not only single gene disorders such as CF are potential candidates for gene therapy, but also cancer and chronic lung diseases characterized by an imbalance of damaging and protective mechanisms. This review summarizes the recent advances in the development of more efficient gene transfer systems and highlights areas of clinical application of gene therapy.

Animals↗

PubMed2006

Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls.

The currently accepted approach to treatment of idiopathic pulmonary fibrosis (IPF) is based on the assumption that it is a chronic inflammatory disease, and most available antiinflammatory drugs target numerous biological processes involving multiple genes, but are not often beneficial. More novel therapeutic strategies take recent findings about the underlying molecular mechanisms of fibrogenesis into account, and ongoing and as yet unpublished clinical trials in IPF aim to block single gene targets believed to play major roles in disease progression. Characterization of the mechanisms involved in the pathogenesis of IPF has largely come from the use of animal disease models in rodents. Most data suggest, from among the different factors, a prominent role for the transforming growth factor (TGF)-beta1 and platelet-derived growth factor pathways. Inflammation is a critical element of the initiation of fibrosis and data indicate that the Smad pathway is a necessary link to fibrosis through TGF-beta and Smad3 signaling, which introduces matrix regulation as a new target for therapeutic intervention. Regardless, gene targeted therapy has numerous pitfalls that have to be addressed before we see a real therapeutic advance.

Clinical Trials as Topic↗

PubMed2006

Smad3 signaling involved in pulmonary fibrosis and emphysema.

The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor beta (TGF-beta) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked up-regulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-beta and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.

Animals↗

PubMed2005

TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis.

Transient adenovirus-mediated gene transfer of IL-1beta (AdIL-1beta), a proinflammatory cytokine, induces marked inflammation and severe and progressive fibrosis in rat lungs. This is associated with an increase in TGF-beta1 concentration in bronchoalveolar lavage (BAL) fluid. TGF-beta1 is a key cytokine in the process of fibrogenesis, using intracellular signaling pathways involving Smad2 and Smad3. In this study we investigate whether inflammation induced by IL-1beta is able to independently induce lung fibrosis in mice deficient in the Smad3 gene. Seven days after AdIL-1beta administration, similar levels of IL-1beta transgene are seen in BAL in both wild-type (WT) and knockout (KO) mice, and BAL cell profiles demonstrated a similar marked neutrophilic inflammation. Phospho-Smad2 staining was positive in areas of inflammation in both WT and KO mice at day 7. By day 35 after transient IL-1beta expression, WT mice showed marked fibrosis in peribronchial areas, quantified by picrosirius red staining and morphometry. However, there was no evidence of fibrosis or collagen accumulation in IL-1beta-treated KO mice, and peribronchial areas were not different from KO mice treated with the control adenovector. TGF-beta1 and phospho-Smad2 were strongly positive at day 35 in fibrotic areas observed in WT mice, but no such staining was detectable in KO mice. The IL-1beta-induced chronic fibrotic response in mouse lungs is dependent on Smad3. KO and WT animals demonstrated a similar inflammatory response to overexpression of IL-1beta indicating that inflammation must link to the Smad3 pathway, likely through TGF-beta, to induce progressive fibrosis.

Activin Receptors, Type I↗

PubMed2005

Transforming growth factor-beta: importance in long-term peritoneal membrane changes.

We have provided evidence from adenovirus-mediated gene transfer to the peritoneum that transforming growth factor-beta1 mimics many of the functional and structural changes in the peritoneum in patients on long-term peritoneal dialysis, including fibrosis, increased submesothelial thickness, angiogenesis, increased solute transport, and ultrafiltration dysfunction. We review several key properties of this important fibrogenic molecule.

Humans↗

PubMed2004

Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor.

Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis (IPF) is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta (TGF-beta) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases (ALK). We have used a gene transfer model of progressive TGF-beta1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.

Activin Receptors, Type I↗

PubMed2004

Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis.

Transforming growth factor-beta 1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-beta 1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-beta 1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).

Animals↗

PubMed2004

Connective tissue growth factor is crucial to inducing a profibrotic environment in "fibrosis-resistant" BALB/c mouse lungs.

The individual susceptibility to pulmonary fibrosis (PF) remains a mystery, suggesting a role for genetic predisposition. The pathogenesis of PF involves a multitude of factors mediating crosstalk between various tissue components. Some factors, such as transforming growth factor beta, are recognized as key elements in the process, whereas the role of others, such as connective tissue growth factor (CTGF), is unclear. We investigated if Balb/c mice, known to be fibrosis resistant partly due to lack of CTGF induction upon stimulation with bleomycin, can be transformed into fibrosis-sensitive individuals by generation of a CTGF-rich environment using transient overexpression of CTGF by adenoviral gene transfer (AdCTGF). We show that AdCTGF is not sufficient to cause fibrosis, and that bleomycin challenge results in inflammation, but not fibrosis, in Balb/c mouse lungs. This inflammation is accompanied by lower levels of CTGF and tissue inhibitor of metalloproteinase-1 gene expression compared with fibrosis-prone C57BL/6 mice. However, concomitant administration of AdCTGF and bleomycin leads to a persistent upregulation of tissue inhibitor of metalloproteinase-1 gene and a significant fibrotic response in Balb/c similar to that in C57BL/6 mice. We propose that CTGF is an important mediator in the pathogenesis of PF in that it provides a local microenvironment in the lung that causes individual susceptibility. CTGF should be considered as a novel drug target and as a potential marker for identifying individuals at risk.

Adenoviridae↗

PubMed2003

Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis.

Connective tissue growth factor (CTGF) is felt to be one of the key profibrotic factors and is a downstream effector molecule mediating the action of transforming growth factor (TGF)-beta1, a cytokine known to induce severe and progressive fibrosis. However, the in vivo fibrogenic effect of isolated CTGF expression is not well described. We used adenoviral gene transfer to transiently overexpress CTGF in rat lungs after intratracheal administration and compared it with transient overexpression of active TGF-beta1 delivered by a similar adenovirus vector. This high expression of CTGF over 6-10 days induced a moderate but reversible fibrosis. We observed an increase of fibronectin, procollagen 1a2, and endogenous CTGF gene expression at 14 days, which suggested an indirect activation by CTGF. Tissue inhibitor of metalloproteinase-1 was weakly and transiently upregulated after CTGF exposure. These same genes were robustly and persistently stimulated by TGF-beta1 from Day 3 to Day 21. This data suggested that CTGF may act as a TGF-beta1 cofactor rather than a direct fibrogenic factor. We demonstrate that CTGF overexpression can initiate fibrogenic activity but likely requires the presence of additional factors, such as tissue inhibitor of metalloproteinase-1, to maintain a nonfibrolytic environment and to cause progression of fibrosis.

Adenoviridae↗

PubMed2003

Re-evaluation of fibrogenic cytokines in lung fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic interstitial lung disease which results in end-stage fibrosis. The pathogenesis is believed to be related to a dysregulation in cross-talk between inflammatory and structural cells, mediated by various cytokines, chemokines and growth factors, which are responsible for the maintenance of tissue homeostasis and which coordinate the response to injury. The large number of mediators involved and the complexity of their interaction makes it difficult to identify the factors responsible for initiation of fibrogenesis and progression to chronicity. Whether a mediator's presence in fibrotic lung is as a result of tissue injury or if it playsan active role in disease onset and progression has been partly answered by the use of transient and/or permanent transgenic and gene knock-out approaches to over-express single factors at a time. Chemokines such as interleukin-8 (IL-8), RANTES, IP-10, MIG or lymphotactin, do not appear to induce fibrosis when over-expressed in rodent lung. Amongst many tested, four cytokines and growth factors have been found to be pro-fibrotic; IL-1beta, which demonstrates marked inflammation, tissue damage and chronic fibrosis, TNF-alpha, which induces inflammation and mild fibrosis, and GM-CSF, which induces moderate inflammation and fibrosis. A common finding with these cytokines are increased lung TGF-beta levels, proportionate to the degree of fibrosis generated, while TGF-beta itself causes minor inflammation but marked progressive chronic fibrosis. A growth factor 'downstream' from the pro-fibrotic effects of TGF-beta, CTGF, is a likely critical mediator. However, over-expression of CTGF produces only mild and reversible fibrosis.

Animals↗

PubMed2002

Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum.

Peritonitis, a common complication of peritoneal dialysis, is followed by acute changes in the function of the peritoneum. The role of inflammatory cytokines in these processes is not clearly identified. We used adenoviral-mediated gene transfer to transiently overexpress interleukin (IL)-1 beta (AdIL-1 beta) or tumor necrosis factor (TNF)-alpha (AdTNF-alpha) in the rat peritoneum then used a modified equilibrium test to study the histological and functional changes. Overexpression of IL-1 beta or TNF-alpha led to an acute inflammatory response. Both inflammatory cytokines induced an early expression of the angiogenic cytokine, vascular endothelial growth factor, along with increased expression of the profibrotic cytokine, transforming growth factor-beta1, along with fibronectin expression and collagen deposition in peritoneal tissues. Both inflammatory cytokines induced angiogenesis, increased solute permeability, and ultrafiltration dysfunction at earlier time points. Changes in structure and function seen in AdTNF-alpha-treated animals returned to normal by 21 days after infection, whereas AdIL-1 beta-treated animals had persistently increased vasculature with submesothelial thickening and fibrosis. This was associated with up-regulation TIMP-1. TNF-alpha or IL-1 beta both induce acute changes in the peritoneum that mimic those seen in peritoneal dialysis patients who experience an episode of peritonitis. These functional changes were associated with early angiogenesis that resolved rapidly after exposure to TNF-alpha. IL-1 beta exposure, however, led to a different response with sustained vascularization and fibrosis. IL-1 beta inhibition may be a therapeutic goal in acute peritonitis to prevent peritoneal damage.

Adenoviridae↗

PubMed2002

Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains.

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in the interstitium, resulting in impaired lung function and respiratory failure. Investigation of the differences in individual susceptibility to the development of fibrosis may help to detect patients that are at risk to fibrosis when exposed to fibrogenic stimuli. In this study we used adenoviral gene transfer to transiently expose a fibrosis-prone (C57BL/6) and a fibrosis-resistant (Balb/c) mouse strain to high levels of active transforming growth factor (TGF)-beta1, a key profibrotic cytokine. Balb/c mice developed significantly less fibrosis compared with C57BL/6 mice in response to active TGF-beta1 despite higher levels of the transgene protein in the lung. This was not due to a general unresponsiveness of cells to TGF-beta1, because primary fibroblasts of both strains increased collagen synthesis upon stimulation with TGF-beta1 in vitro to the same degree. However, TGF-beta1 induced a strong upregulation of tissue inhibitor of metalloprotease-1 gene in pulmonary fibroblasts as well as in lungs of C57BL/6 mice, in contrast to a weak induction in Balb/c mice. These findings suggest that the differences in susceptibility to pulmonary fibrosis are downstream from TGF-beta1 and that fibrosis-prone individuals may have an altered collagen metabolism in the lungs that is balanced toward a "nondegrading" environment.

Adenoviridae↗

PubMed2002

Fatal pericardial tamponade after Wallstent implantation for malignant superior vena cava syndrome.

PURPOSE: To report a rare, fatal complication of superior vena cava Wallstent implantation. CASE REPORT: A 59-year-old man presenting with superior vena cava syndrome caused by small-cell lung cancer underwent stent implantation of 2 kissing Wallstents >1.5 cm above the right atrium. Despite correct stent deployment, vessel perforation occurred in a section not encased by tumor, which led to fatal pericardial tamponade shortly after the procedure. Autopsy revealed perforation of a stent strut through the caval wall into the pericardial space. Anatomical and methodological reasons are discussed. CONCLUSIONS: The interventionist should be aware of this rare complication. Alternative stent designs avoiding the sharp ends of Wallstents and Palmaz stents should be considered.

Blood Vessel Prosthesis Implantation↗

PubMed2002

Antiangiogenic and antifibrotic gene therapy in a chronic infusion model of peritoneal dialysis in rats.

To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-beta-inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (-3.1 versus -7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 microg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-beta-inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.

Angiostatins↗

PubMed2001

A new direction in the pathogenesis of idiopathic pulmonary fibrosis?

A recent review article suggested that idiopathic pulmonary fibrosis (IPF) is a disease that is associated more with abnormal wound healing than with inflammation. Data derived from transgenic and gene transfer rodent models suggest that lung inflammation may be a necessary but insufficient component of IPF, and that at some point in the natural history of the disease IPF becomes no longer dependent on the inflammatory response for propagation. Altered microenvironment and involvement of epithelial cell/mesenchymal cell interaction are the most likely contributors to the pathogenesis of this chronic progressive disorder.

Animals↗

PubMed2001

Gene transfer of transforming growth factor-beta1 to the rat peritoneum: effects on membrane function.

Long-term peritoneal dialysis is limited by physiologic changes in the peritoneum that lead to ultrafiltration failure. To determine the role of profibrotic cytokines in the alteration of peritoneal transport, a rodent model of transforming growth factor-beta (TGF-beta)-mediated peritoneal fibrosis was established. An adenoviral vector driving the active form of TGF-beta1 (AdTGFbeta1) was administered intraperitoneally, and peritoneal structure and function were evaluated for 28 d after infection. Seven days after AdTGFbeta1 infection, thickening of the peritoneum, with cellular proliferation and increased vascularization, was noted. By day 28, there was persistent thickening and extensive collagen deposition. The mesenteric collagen content was significantly elevated, compared with control adenovirus-treated animals, 21 d after infection (2.9 versus 1.8 mg hydroxyproline/g tissue, P = 0.006). Blood vessel density, as measured using factor VIII immunohistochemical analyses, was significantly increased from day 4 to day 21 but decreased by day 28. Animals infected with AdTGFbeta1 demonstrated increased transport of solutes and decreased net ultrafiltration, which was maximal on day 7 and returned to baseline levels by day 28. It was demonstrated in vitro and in vivo that TGF-beta1 induced production of vascular endothelial growth factor. Overexpression of TGF-beta1 after adenovirus-mediated gene transfer causes peritoneal fibrosis, neoangiogenesis, and increased peritoneal membrane solute transport. This model should allow further delineation of the relative contributions of profibrotic and angiogenic cytokines to changes in peritoneal function and may lead to potential new interventions for peritoneal membrane failure.

Animals↗