Biomedical subjects

Y P Moodley

Publications and source records attributed to Y P Moodley.

5 recordsLinked to original sources

PubMed2001

Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins.

Myofibroblasts, characterised by high expression of alpha-smooth muscle actin (alpha-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via alpha v and beta 1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in alpha-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins alpha v, beta 1, alpha v beta 3 and alpha v beta 5 induced the expression of alpha-SMA and its organization into stress fibers. Expression of alpha-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of alpha-SMA. The expression and organization of alpha-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of alpha-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of alpha-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.

Actins↗

PubMed2001

Exhaled nitric oxide is elevated in patients with progressive systemic sclerosis without interstitial lung disease.

BACKGROUND: Progressive systemic sclerosis (PSS) is a multisystem disorder of unknown etiology. Interstitial lung disease (ILD) is a major cause of mortality in this condition, and a major challenge in this regard is to identify parameters that would predict the onset or progression of ILD in patients with PSS. Abnormal cellularity of BAL fluid (BALF) has been demonstrated in patients with PSS without ILD. STUDY OBJECTIVES: We investigated exhaled nitric oxide (NO) as a noninvasive marker of pulmonary inflammation in patients with PSS with and without clinical and radiologic evidence of ILD. This was compared with the cellularity of BALF. Our hypothesis was that exhaled NO was elevated in patients with PSS without ILD who had abnormal BALF cellularity. SETTING: Pulmonology and rheumatology units of a university-based, tertiary referral hospital in Durban, South AFRICA: STUDY METHODS: Exhaled NO was measured using a chemiluminescence analyzer in 12 patients with PSS and ILD and in 12 patients without clinical or radiologic evidence of ILD and in 30 healthy control subjects. BAL was performed in patients with PSS with and without the presence of ILD and in six healthy control subjects. RESULTS: Subclinical inflammation was confirmed by increased inflammatory cell counts in BALF from patients with PSS without ILD. Exhaled NO (mean [SEM]) was elevated in patients with PSS without ILD at 9.6 (0.7) parts per billion (ppb) compared to patients with PSS and ILD at 6.2 (0.6) ppb (p < 0.001) and healthy control subjects at 6.3 (0.2) ppb (p < 0.001). CONCLUSION: Exhaled NO may therefore be an important noninvasive surrogate marker of inflammation in patients with PSS without ILD.

Adult↗

PubMed2000

Correlation of CD4:CD8 ratio and tumour necrosis factor (TNF)alpha levels in induced sputum with bronchoalveolar lavage fluid in pulmonary sarcoidosis.

BACKGROUND: An increased CD4:CD8 lymphocyte ratio and raised cytokine levels in bronchoalveolar lavage (BAL) fluid are characteristic of pulmonary sarcoidosis. Sputum induction has been used as a non-invasive tool for investigating the airways and may be useful in investigating inflammation in patients with sarcoidosis in whom endobronchial, peribronchial, and parenchymal inflammation is present. This study aimed to correlate the total and differential cell counts, CD4:CD8 ratio, and tumour necrosis factor (TNF)alpha levels between induced sputum and BAL fluid in patients with pulmonary sarcoidosis. METHODS: Fourteen patients with newly diagnosed biopsy proven sarcoidosis and six healthy controls were investigated. Sputum induction and BAL was carried out at the initial visit and repeated following six months of treatment with oral prednisone. RESULTS: There was no correlation of differential cell counts between induced sputum and BAL fluid. The CD4:CD8 ratio in induced sputum correlated strongly with that in BAL fluid (5.5 (0. 4:1) versus 4.4 (0.2:1); r = 0.8, p<0.001) and the fall in the ratio following six months of treatment in sputum paralleled that in BAL fluid (3.4 (0.2:1) versus 2.4 (0.2:1)). The TNF alpha levels in sputum also correlated with levels in the BAL fluid (11.9 (1.5) pg/ml versus 17.6 (2.7) pg/ml; r = 0.8, p<0.001). The fall in sputum TNF alpha levels following six months of treatment paralleled the fall in BAL fluid levels (6.7 (0.9) pg/ml versus 11.6 (1.3) pg/ml). CONCLUSIONS: The CD4:CD8 ratio and TNF alpha levels in induced sputum correlated with those in BAL fluid and paralleled changes with treatment. Induced sputum may therefore be a non-invasive surrogate for certain parameters in BAL fluid in patients with sarcoidosis.

Adult↗

PubMed2000

Neutrophils in induced sputum arise from central airways.

A high neutrophil count is often found in induced sputum compared to bronchoalveolar lavage fluid (BALF). This study investigated whether such a high neutrophil count may be a response to inhaled hypertonic saline or that the airway compartment sampled by induced sputum has a higher concentration of neutrophils than BALF. Saliva and induced sputum samples were taken at 10 and 20 min following inhalation of 3% hypertonic saline from an ultrasonic nebulizer in 12 healthy nonsmoking subjects. Four days later the 12 subjects underwent bronchoscopy (six following inhalation with 3% saline). Tracheal, proximal bronchial secretions, bronchial washings and BALF samples were obtained. The neutrophil count (% total leukocytes) increased significantly in saliva at 10 and 20 min post nebulization with 3% saline, although there was no change in neutrophils in induced sputum at 10 and 20 min. There was no significant difference in neutrophil count in the subjects who inhaled 3% saline as compared to those who did not, in secretions from the trachea, proximal bronchi, bronchial washings and BALF. Neutrophil counts were significantly higher in the trachea, proximal bronchi and bronchial washings as compared to BALF (p<0.001). It is concluded that neutrophil counts in healthy subjects increase from the peripheral towards the proximal airways, in the absence of hypertonic saline-induced changes. This suggests that the relatively high neutrophil count in induced sputum arises from the proximal airways and is not a response to inhaled hypertonic saline during the procedure.

Adult↗

PubMed1999

Nitric oxide levels in exhaled air and inducible nitric oxide synthase immunolocalization in pulmonary sarcoidosis.

Cytokines such as tumour necrosis factor-alpha and interferon gamma are associated with active pulmonary inflammation in sarcoidosis and they upregulate inducible nitric oxide synthase (iNOS). The objectives of this study were to examine iNOS upregulation in sarcoidosis by showing raised exhaled nitric oxide and increased iNOS activity in lung biopsy specimens of these patients utilizing immunohistochemistry. Exhaled NO was measured by a chemiluminescence analyser in 12 patients with newly diagnosed biopsy-proven sarcoidosis before and after 6 weeks of corticosteroid therapy. Lung biopsy specimens from these patients were subjected to immunohistochemical staining with a specific iNOS antibody. Exhaled NO was raised in newly diagnosed sarcoidosis (mean+/-SEM): 9.8+/-0.4 versus 4.1+/-0.2 parts per billion (ppb) in 21 healthy controls, p<0.001; and fell significantly after 6 weeks treatment with corticosteroids to 5.9+/-1.4 ppb; p<0.01. There was no correlation between exhaled NO and other markers of disease activity. Immunohistochemical staining demonstrated iNOS activity in respiratory epithelium and granulomas in patients with sarcoidosis. Exhaled nitric oxide is raised in patients with active pulmonary sarcoidosis and may be a result of inducible nitric oxide synthase upregulation. The fall in exhaled nitric oxide following corticosteroid therapy may reflect inhibition of inducible nitric oxide synthase in the respiratory epithelium and granulomas.

Adult↗