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Biomedical subjects

N Khalil

Publications and source records attributed to N Khalil.

At least 19 recordsLinked to original sources
PubMed2002

Characterization of the Oum Er Rbia (Morocco) high basin karstic water sources by using solid state nuclear track detectors and radon as a natural tracer.

Uranium and thorium contents as well as radon alpha-activities per unit volume were evaluated inside different water samples by using a method based on calculating the CR-39 and LR-115 type II solid state nuclear track detectors (SSNTDs) detection efficiencies for the emitted alpha-particles and measuring the resulting track density rates. The validity of the SSNTD technique utilized was checked by analysing uranyl nitrate (UO2(NO3)26H2O) standard solutions. A relationship between water radon concentration and water transmission of different water sources belonging to two regions of the Middle Atlas (Morocco) water reservoir was found. The influence of the water flow rate as well as the permeability and fracture system of the host rocks of the sources studied was investigated.

Morocco↗
PubMed2001

Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by subpleural fibrosis that progresses to involve all areas of the lung. The expression of transforming growth factor-beta1 (TGF-beta 1), a potent regulator of connective tissue synthesis, is increased in lung sections of patients with IPF. TGF-beta 1 is generally released in a biologically latent form (L-TGF-beta 1). Before being biologically active, TGF-beta must be converted to its active form and interact with both TGF-beta receptors type I and II (T beta R-I and T beta R-II). TGF-beta latency binding protein 1 (LTBP-1), which facilitates the release and activation of L-TGF-beta 1, is also important in the biology of TGF-beta 1. METHODS: Open lung biopsy samples from patients with IPF and normal controls were examined to localise T beta R-I, T beta R-II, and LTBP-1. Alveolar macrophages (AM) and bronchoalveolar lavage (BAL) fluid were examined using the CCL-64 bioassay to determine if TGF-beta is present in its active form in the lungs of patients with IPF. RESULTS: Immunoreactive L-TGF-beta 1 was present in all lung cells of patients with IPF except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced IPF. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with IPF secreted 1.6 (0.6) fmol and 4.1 (1.9) fmol active TGF-beta, respectively, while AM from the lower lobes of control patients secreted no active TGF-beta (p< or =0.01 for TGF-beta in the conditioned media from AM obtained from the lower lobes of IPF patients v normal controls). The difference in percentage active TGF-beta secreted by AM from the lower lobes of patients with IPF and the lower lobes of control patients was significant (p< or =0.01), but the difference between the total TGF-beta secreted from these lobes was not significant. The difference in active TGF-beta in conditioned media of AM from the upper and lower lobes of patients with IPF was also not statistically significant. BAL fluid from the upper and lower lobes of patients with IPF contained 0.7 (0.2) fmol and 2.9 (1.2) fmol active TGF-beta, respectively (p< or =0.03). The percentage of active TGF-beta in the upper and lower lobes was 17.6 (1.0)% and 78.4 (1.6)%, respectively (p< or =0.03). In contrast, BAL fluid from control patients contained small amounts of L-TGF-beta. Using immunostaining, both T beta R-I and T beta R-II were present on all cells of normal lungs but T beta R-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with IPF. TGF-beta 1 inhibits epithelial cell proliferation and a lack of T beta R-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both T beta Rs on fibroblasts is likely to result in a response to TGF-beta 1 for synthesis of connective tissue proteins. Our findings show that biologically active TGF-beta 1 is only present in the lungs of patients with IPF. In addition, the effects of TGF-beta 1 on cells may be further regulated by the expression of T beta Rs. CONCLUSION: Activation of L-TGF-beta 1 and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and fibrosis in IPF.

Bronchoalveolar Lavage Fluid↗
PubMed2001

Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen.

In severe or chronic asthma, there is an increase in airway smooth muscle cell (ASMC) mass as well as an increase in connective tissue proteins in the smooth muscle layer of airways. Transforming growth factor-beta (TGF-beta) exists in three isoforms in mammals and is a potent regulator of connective tissue protein synthesis. Using immunohistochemistry, we had previously demonstrated that ASMCs contain large quantities of TGF-beta1-3. In this study, we demonstrate that bovine ASMC-derived TGF-beta associates with the TGF-beta latency binding protein-1 (LTBP-1) expressed by the same cells. The TGF-beta associated with LTBP-1 localizes TGF-beta extracellularly. Furthermore, plasmin, a serine protease, regulates the secretion of a biologically active form of TGF-beta by ASMCs as well as the release of extracellular TGF-beta. The biologically active TGF-beta released by plasmin induces ASMCs to synthesize collagen I in an autocrine manner. The autocrine induction of collagen expression by ASMCs may contribute to the irreversible fibrosis and remodeling seen in the airways of some asthmatics.

Animals↗
PubMed2001

Post translational activation of latent transforming growth factor beta (L-TGF-beta): clinical implications.

Transforming growth factor-betas (TGF-betas) are multifunctional cytokines that exist in 3 isoforms in mammals. The TGF-betas are ubiquitously expressed and all isoforms are secreted as biologically inactive precursors called latent TGF-beta (L-TGF-beta). L-TGF-betas are generally not effective molecules because they are unable to interact with their receptors. However, the removal of or conformational change of the precursor protein called the latency associated peptide (LAP) results in the generation of biologically active TGF-beta. In vitro active TGF-beta has many biological effects but from a clinical point of view one of the most recognized associations of aberrant TGF-beta production is with diseases characterized by enhanced connective tissue synthesis. Recently a number of observations in the context of fibrotic disorders suggest mechanisms of activation of L-TGF-beta1 in vivo. The recognition of mechanisms that activate L-TGF-beta1 in vivo offers the possibility of interfering with the activation of L-TGF-beta1 for therapeutic purposes.

Animals↗
PubMed2000

Evidence for the involvement of dietary lipids on the modulation of transforming growth factor-beta1 in the platelets of male rats.

Transforming growth factor beta1 (TGF-beta1), a multifunctional cytokine participates in the proliferation and differentiation of various cell types. Platelets are an important source of TGF-beta1 and are physiologically linked to a variety of chronic illnesses including cancer, heart disease and inflammation. It is well known that dietary lipids modulate platelet function. Whether dietary lipids affect growth factor status of platelets is not known. This study addresses the effect of dietary lipids on TGF-beta1 status of the platelets. Male 8 month-old Sprague Dawley rats were allocated to different diet groups. The high fat diets ( 18% by weight) comprising of high fat beef tallow (HFB), high fat corn oil (HFC), high fat fish oil (HFF) and high fat olive oil (HFO) and one low fat diet containing low fat soybean oil (LFS) (5% by weight) were fed to the experimental animals for 6 weeks. The TGF-beta1 status in the platelet lysate was assessed by using the CCL-64 mink lung cell bioassay and by Western blot analysis. Platelet lysates were evaluated for their ability to inhibit the growth of the CCL-64 mink lung cells, unexpectedly platelet lysates stimulated growth. The stimulatory effect of platelet lysate was in the order HFF > HFO > HFB > HFC > LFS. Acidification of the lysates to activate the latent form of TGF-beta1 resulted in the loss of the growth stimulatory potential of the platelet lysates in all the groups. Western blot analysis of the platelet lysates to detect the level of TGF-beta1 protein demonstrated that HFB diet group had the highest level of TGF-beta1 and the HFC diet group had the lowest level of TGF-beta1 and were significantly different (p < 0.05) as compared to the other three diet groups. These findings demonstrate that dietary lipids varying in their fatty acid composition, profoundly affect the level of growth modulating constituents of the platelets. Further studies are warranted to refine our understanding of the effect of dietary constituents on the physiology of the platelets.

Animals↗
PubMed2000

A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat.

Transforming growth factor (TGF)-beta1 is an important regulator of inflammation and fibrosis. TGF-beta1 is usually secreted as a biologically latent protein called latent TGF-beta1 (L-TGF-beta1). L-TGF-beta1 has no biologic effect unless L-TGF-beta1 is converted to its active form. Using a well-recognized model of lung injury induced by the antineoplastic antibiotic bleomycin (Blm), we demonstrated that 7 d after intratracheal Blm administration, total lung TGF-beta was maximally increased. This induction was due to TGF-beta1 production by alveolar macrophages that, when explanted, generated increased quantities of L-TGF-beta1 complexed with the glycoprotein thrombospondin (TSP)-1. The TSP-1/L-TGF-beta1 complex was associated with CD36, a receptor for TSP-1. The association of TSP-1/L-TGF-beta1 to CD36 was critical for plasmin-mediated release of mature TGF-beta1. In this paper we show that, compared with administration of Blm by itself, when a synthetic peptide of CD36 between amino acids 93 and 110 is given concomitantly with Blm to rats, alveolar macrophages generate markedly less active TGF-beta1, the rats gain weight more rapidly, and there is less inflammation, collagen I and III, and fibronectin synthesis. These findings demonstrate a novel in vivo mechanism of activation of L-TGF-beta1 in lung injury and the importance of alveolar macrophage- derived active TGF-beta1 in the pathogenesis of pulmonary inflammation and fibrosis.

Animals↗
PubMed2000

A role for hyaluronan in macrophage accumulation and collagen deposition after bleomycin-induced lung injury.

Elevated concentrations of hyaluronan (HA) are associated with the accumulation of macrophages in the lung after injury. We have investigated the role of HA in the inflammatory and fibrotic responses to lung injury using the intratracheal instillation of bleomycin in rats as a model. After bleomycin-induced lung injury, both HA content in bronchoalveolar lavage (BAL) and staining for HA in macrophages accumulating in injured areas of the lung were maximal at 4 d. Increased HA in BAL correlated with increased locomotion of isolated alveolar macrophages. HA-binding peptide was able to specifically block macrophage motility in vitro. Importantly, systemic administration of HA-binding peptide to rats before injury not only decreased alveolar macrophage motility and accumulation in the lung, but also reduced lung collagen alpha (I) messenger RNA and hydroxyproline contents. We propose a model in which HA plays a critical role in the inflammatory response and fibrotic consequences of acute lung injury.

Amino Acid Sequence↗
PubMed1999

Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36.

Transforming growth factor-beta-1 (TGF-beta1) is secreted by cells in a latent form (L-TGF-beta1) noncovalently bound to a latency-associated peptide. Activated alveolar macrophages obtained from rat lungs after bleomycin-induced pulmonary injury released increased amounts of active TGF-beta1 as well as plasmin, a protease, and thrombospondin-1 (TSP-1), a trimeric glycoprotein. Previously we had demonstrated that plasmin was critical to the activation of L-TGF- beta1. In the present study we demonstrated that TSP-1 is also important for the activation of L-TGF- beta1 because the activation can be inhibited by anti-TSP-1 monoclonal antibody. Proteins obtained from alveolar macrophage cell lysates immunoprecipitated with antibodies specific for TSP-1 were identified on immunoblots as LAP and TGF-beta1, indicating that TSP-1/L-TGF-beta1 complexes are present on alveolar macrophages. However, in the presence of plasmin both latency-associated peptide and TGF-beta1 were decreased in the same cell lysates, indicating that L-TGF-beta1 associated with TSP-1 is released by plasmin. Using immunofluorescence and antibodies to TGF-beta1 and CD36, a receptor for TSP-1, there was colocalization of TGF-beta1 with CD36. Because TSP-1 but not TGF-beta1 is a natural ligand for CD36, these findings suggest that the L-TGF-beta1 in a complex with TSP-1 localizes to the macrophage cell surface when TSP-1 interacts with its receptor, CD36. Furthermore, the association of TSP-1/L-TGF-beta1 complex with CD36 is necessary to the activation of L-TGF-beta1 because antibodies to CD36 prevent the colocalization of TGF-beta1 with CD36 as observed by immunofluorescence and inhibit activation of the L-TGF-beta1 by explanted alveolar macrophages. These findings suggest that activation of L-TGF-beta1 by plasmin occurs at the cell surface of activated alveolar macrophages and requires a TSP-1/CD36 interaction.

Animals↗
PubMed1999

TGF-beta: from latent to active.

The transforming growth factor-betas (TGF-betas) are synthesized as precursor proteins that are modified intracellularly prior to secretion. One of the most relevant intracellular modifications is the cleavage of the C-terminal pro-region from the N-terminal portion of the protein. The C-terminal pro-region is referred to as the latency-associated peptide (LAP) while the N-terminal region is called the mature TGF-beta or active TGF-beta. However, with some exceptions the LAP noncovalently associates with the mature TGF-beta prior to secretion. When the mature TGF-beta is associated with the LAP it is called L-TGF-beta and cannot interact with its receptor and has no biological effect. The TGF-betas and their receptors are very ubiquitously expressed, suggesting that the regulation of TGF-beta activity is likely to be complex and multifactorial. However, one of the most important means of controlling the biological effects of TGF-beta is the regulation of converting L-TGF-beta to active TGF-beta. The current literature supports two major mechanisms of activation of L-TGF-beta and suggests that the mechanism of activation of L-TGF-beta may be varied and context-dependent. For TGF-beta to become biologically active the LAP has to be either released from its associations with L-TGF-beta or undergo conformational change such that the LAP is not released from the L-TGF-beta complex but exposes the TGF-beta receptor binding site. Since TGF-beta has been associated with the pathogenesis of numerous diseases, the various mechanisms of activation of L-TGF-beta in context offer the possibility of controlling TGF-beta activity localized to the organ of involvement and to a more specific disease process.

Gene Expression Regulation↗
PubMed1998

Use of mouth pressure twitches induced by cervical magnetic stimulation to assess voluntary activation of the diaphragm.

There is a need for a simple method to assess the adequacy of diaphragm activation during voluntary inspiratory efforts in patients with suspected respiratory muscle weakness. We have compared mouth (Pmo,t), oesophageal (Poes,t) and transdiaphragmatic (Pdi,t) twitch pressure elicited by cervical magnetic stimulation (CMS) in five normal men (mean (SD) age 32.2 (1.8) yrs) on two separate study days. Single magnetic stimuli were delivered at functional residual capacity during relaxation and during graded voluntary inspiratory efforts against a closed airway. As voluntary-effort transdiaphragmatic and oesophageal pressure increased, Pdi,t and Poes,t decreased linearly (r range, respectively, 0.82-0.98 and 0.87-0.95). During relaxation, Pmo,t was unreliable due to the poor transmission of intrathoracic pressure, but during inspiratory efforts, the relation between voluntary mouth pressure and Pmo,t was also linear (r range 0.84-0.95). On average, our subjects voluntarily generated 99, 100 and 102% of the maximum transdiaphragmatic, oesophageal and mouth pressures predicted by the respective linear regression equations. Pmo,t was correlated to both Poes,t and Pdi,t during inspiratory efforts, but not during relaxation. These studies confirm that twitch pressures induced by CMS during inspiratory efforts can be assessed at the mouth in normal subjects, providing a simple and non-invasive technique for assessing diaphragm activation during voluntary inspiratory efforts. Potentially, this technique could be made more sensitive and accurate and applied to detect submaximal efforts in patients.

Adult↗
PubMed1996

Foot dystonia and lumbar canal stenosis.

We describe a patient who developed involuntary, painless, dystonic contraction of the toes of the right foot on standing or walking. The development of this abnormal movement had been preceded by sensory disturbance on the soles of both feet, triggered by dorsiflexion of the feet. Examination showed that weight bearing on the right foot and walking brought on clawing of the toes of the right foot, which was relieved within seconds of taking pressure off the right foot. There was sensory and reflex evidence of bilateral S1 root disturbance confirmed by electrophysiology. Magnetic resonance imaging of the lumbar spine showed marked stenosis of the lumbar canal with compression of the L5 and S1 nerve roots bilaterally. The patient underwent a lumbar laminectomy with nerve root exit foramina decompression, which abolished the foot dystonia and has considerably improved the sensory disturbance. This case demonstrates that lumbar canal stenosis and/or nerve root compression, may be responsible for foot dystonia. Amelioration of the abnormal movement by surgical decompression argues strongly in favour of this hypothesis.

Decompression, Surgical↗
PubMed1996

TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study.

Although it is recognized that three isoforms of transforming growth factor-beta (TGF-beta) exist in mammals, their expression, distribution, and function in injury and repair are not well characterized. Using immunohistochemistry and antibodies to synthetic peptides of TGF-beta 1, TGF-beta 2, and TGF-beta 3, we determined the distribution of TGF-beta isoforms in lung sections with acute and chronic lesions of idiopathic pulmonary fibrosis (IPF), chronic asbestosis and hypersensitivity pneumonitis, as well as non-specific pneumonitis. In lung sections with advanced pulmonary fibrosis and honeycombing, irrespective of the diagnosis, TGF-beta 1 was prominently expressed in epithelial cells and macrophages and was found to be associated with the extracellular matrix. In lungs with early lesions of IPF and only inflammatory changes, TGF-beta 1 was present in alveolar macrophages but TGF-beta 1 was not present in epithelial cells. Small amounts of matrix-associated TGF-beta 1 were present subepithelially in areas of lung sections from patients with IPF with minimal inflammation and no fibrosis. In normal lungs with no evidence of inflammation or fibrosis TGF-beta 1 was not seen in alveolar macrophages, epithelial cells, or extracellularly. TGF-beta 2 and TGF-beta 3 were expressed in alveolar macrophages, epithelial cells, and smooth muscle cells of vessels and bronchi of normal lungs and lungs with both inflammatory and fibrotic changes. Our findings suggest that while TGF-beta 2 and TGF-beta 3 are ubiquitously expressed in the lung, TGF-beta 1 is expressed in epithelial cells of fibrotic lungs where the presence of TGF-beta 1 is not disease-specific but an indication of the chronicity of the injury.

Adult↗
PubMed1996

Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury.

Transforming growth factor beta s (TGF-beta s) are 25-kD multifunctional proteins that regulate inflammation and connective tissue synthesis. With rare exception TGF-beta 1 is secreted noncovalently bound to a latency-associated peptide (LAP) that renders the mature TGF-beta 1 biologically inactive. An important mechanism for the control of TGF-beta 1 action is the regulation of the post-translational processing that removes the LAP from the mature peptide and renders it biologically active. In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we have demonstrated that explanted alveolar macrophages secrete progressively increasing quantities of a biologically active form of TGF-beta 1, the secretion of which was maximal 7 days after bleomycin administration. Thereafter, there was a rapid decline in the secretion of the active form of TGF-beta 1, whereas the latent form continued to be secreted in elevated quantities. Plasmin, a serine protease, was transiently generated by the same bleomycin-activated alveolar macrophages and paralleled the rise in active TGF-beta 1. When alpha 2-antiplasmin, an inhibitor of plasmin, was added to cultures of alveolar macrophages, the post-translational activation of L-TGF-beta 1, was totally abrogated. When plasmin was added to alveolar macrophages in culture, there was complete activation of the L-TGF-beta 1 that had been secreted during the culture period. However, there was no effect of plasmin on the same alveolar macrophage-derived L-TGF-beta 1 in cell-free conditioned media. Our findings suggest that the secretion of an active form of TGF-beta 1 by alveolar macrophages is regulated by the generation of plasmin and requires that the alveolar macrophages be present. Because the diminution of active TGF-beta 1 coincides with the resolution of inflammation, this suggests that the availability of plasmin regulates the biologically active form of TGF-beta 1, and thus, the inflammation seen after bleomycin-induced lung injury.

Animals↗