Alana Majors - Academia.edu (original) (raw)

Papers by Alana Majors

Research paper thumbnail of Pertussis toxin and genistein inhibit cell proliferation but not collagen synthesis by arterial smooth muscle cells

Research paper thumbnail of Royal academy of medicine in Ireland international conference on homocysteine metabolism from basic science to clinical medicine

Irish Journal of Medical Science, 1995

VITAMIN B 12, S-MMA AND S-HCY - A POPULATION STUDY OF MEN AND WOMEN AGED 70 YEARS OR OLDER K. Bjr... more VITAMIN B 12, S-MMA AND S-HCY - A POPULATION STUDY OF MEN AND WOMEN AGED 70 YEARS OR OLDER K. Bjrrkegren. Department of Family Medicine, Uppsala University, Uppsala, Sweden. In an industrial community with 9.300 inhabitants, in central Sweden, a ...

Research paper thumbnail of Nitric oxide alters hyaluronan deposition by airway smooth muscle cells

PLOS ONE, 2018

Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matr... more Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matrix, including changes in hyaluronan (HA) deposition. However, little is known about the factors that modulate its deposition or the potential consequences. Asthmatics with high levels of exhaled nitric oxide (NO) are characterized by greater airway reactivity and greater evidence of airway inflammation. Based on these data and our previous work we hypothesized that excessive NO promotes the pathologic production of HA by airway smooth muscle cells (SMCs). Exposure of cultured SMCs to various NO donors results in the accumulation of HA in the form of unique, cable-like structures. HA accumulates rapidly after exposure to NO and can be seen as early as one hour after NO treatment. The cable-like HA in NO-treated SMC cultures supports the binding of leukocytes. In addition, NO produced by murine macrophages (RAW cells) and airway epithelial cells also induces SMCs to produce HA cables when grown in co-culture. The modulation of HA by NO appears to be independent of soluble guanylate cyclase. Taken together, NO-induced production of leukocyte-binding HA by SMCs provides a new potential mechanism for the non-resolving airway inflammation in asthma and suggests a key role of non-immune cells in driving the chronic inflammation of the submucosa. Modulation of NO, HA and the consequent immune cell interactions may serve as potential therapeutic targets in asthma.

Research paper thumbnail of Growth hormone injections improve bone quality in OI mice

Research paper thumbnail of Characterization, Distribution and Putative Function of ADAMTSL4, an Extracellular Protein Mutated in Recessive Ectopia Lentis

Investigative Ophthalmology & Visual Science, 2010

Research paper thumbnail of Homocystetne and other thiols are non-mttogenic in balamm-replete aortic smooth muscle cells

Research paper thumbnail of TNF-stimulated gene 6 promotes formation of hyaluronan–inter-α-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness

Journal of Biological Chemistry

Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (A... more Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-␣-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptor binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological HA-HC matrix. However, the role of TSG-6 in acute airway inflammation is not well understood. Here, we hypothesized that TSG-6 is essential for the development of HA-and ozone-induced AHR. TSG-6 ؊/؊ and TSG-6 ؉/؉ mice were exposed to ozone or short-fragment HA (sHA), and AHR was assayed via flexiVent. The AHR response to sHA was evaluated in the isolated tracheal ring assay in tracheal rings from TSG-6 ؊/؊ or TSG-6 ؉/؉ , with or without the addition of exogenous TSG-6, and with or without inhibitors of Rho-associated, coiled-coil-containing protein kinase (ROCK), ERK, or PI3K. Smooth-muscle cells from mouse tracheas were assayed in vitro for signaling pathways. We found that TSG-6 deficiency protects against AHR after ozone (in vivo) or sHA (in vitro and in vivo) exposure. Moreover, TSG-6 ؊/؊ tracheal ring non-responsiveness to sHA was reversed by exogenous TSG-6 addition. sHA rapidly activated RhoA, ERK, and Akt in airway smooth-muscle cells, but only in the presence of TSG-6. Inhibition of ROCK, ERK, or PI3K/Akt blocked sHA/TSG-6-mediated AHR. In conclusion, TSG-6 is necessary for AHR in response to ozone or sHA, in part because it facilitates rapid formation of HA-HC complexes. The sHA/TSG-6 effect is mediated by RhoA, ERK, and PI3K/ Akt signaling.

Research paper thumbnail of IL-17A Recruits Rab35 to IL-17R to Mediate PKCα-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility

The Journal of Immunology

Research paper thumbnail of Hyaluronan and Nitric Oxide Collaborate As Inflammatory Mediators in Asthma

Data Revues 00916749 V131i2ss S0091674912028412, Jan 26, 2013

RATIONALE: Lipid rafts in epithelial cell membrane plays multifunctions, including components of ... more RATIONALE: Lipid rafts in epithelial cell membrane plays multifunctions, including components of immune system and important mediators in inflammatory process. But the role of cholesterol, composing lipid rafts, has not been described in the inflammatory response. The aim of this study is to investigate the effect of cholesterol depletion to inflammatory process via expression of interleukin (IL)-8 in airway epithelial cells. METHODS: The human epithelial-like lung carcinoma cell line(A 549) was treated with 0.5% methyl-b-cyclodextrin as a selective cholesterol extractor. IL-8 levels were assessed by enzyme-linked immunosorbent assay (ELISA) and rechecked after cholesterol repletion. Mitogen-activated protein kinase (MAPK) inhibitors were used to find upstream signaling pathway for IL-8 production in cholesterol-depleted cells. RESULTS: IL-8 production in cholesterol-depleted epithelial cells increased in a time-dependent manner. The maximum production of IL-8 recorded at 24 h was almost 3.5 times more than control cells. In addition, it reversed after cholesterol repletion. And IL-8 production decreased followed by pretreatment with extracellular signal-regulated kinase (ERK) inhibitor U0126, but not with JNK inhibitor II or p38 MAPK inhibitor SB202190. CONCLUSIONS: These results suggested that inflammatory responses could be increased in cholesterol-depleted cells, and it was regulated by MAPK signaling system, predominantly by ERK pathway. We concluded that lipid component in airway epithelial cells may play a role in inflammatory process.

Research paper thumbnail of Plasma homocysteine and malondialdehyde are correlated in an age- and gender-specific manner

Metabolism Clinical and Experimental, Nov 1, 2002

Homocysteine is an independent risk factor for peripheral vascular and coronary artery disease. T... more Homocysteine is an independent risk factor for peripheral vascular and coronary artery disease. The exact mechanism by which homocysteine promotes vascular dysfunction is unclear, but it is speculated to involve oxidative stress. Several studies have investigated the role of homocysteine in promoting oxidative stress and have obtained conflicting results. The age and gender of the subject populations in these studies may have influenced the outcome. Therefore, we investigated whether plasma homocysteine concentrations were correlated with plasma malondialdehyde (MDA, a marker of oxidative stress), and if the subject's age and gender affected this correlation. Plasma homocysteine and MDA were measured in 35 premenopausal women, 14 young men, 38 postmenopausal women, and 18 older men. Homocysteine was significantly higher in men than women (P <.01) and in older subjects versus younger. However, MDA was significantly greater only in the young men (P <.01). Furthermore, there was a significant correlation between homocysteine and MDA only in these young men (R(2) = 0.50, P <.01). Lastly, subjects undergoing a methionine load did not exhibit increased MDA despite significant increases in homocysteine. Since oxidative stress correlates with basal homocysteine only in young men and does not increase with acutely increased homocysteine, it is unlikely to be the result of a direct effect of homocysteine.

Research paper thumbnail of Hyaluronan and its heavy chain modification in asthma severity and experimental asthma exacerbation

The Journal of biological chemistry, Jan 24, 2015

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has bee... more Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI) which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity. Our objective was to characterize the levels of HA and HC-HA in asthmatic subjects and to correlate these levels with asthma severity. We determined the levels and distribution of HA and HC-HA (i) from asthmatic and control lung tissue, (ii) in bronchoalveolar lavage fluid obtained from non-severe and severe asthmatics and controls and (iii) in serum and urine from atopic asthmatics after an experimental asthma exacerbation. HC-HA distribution was observed (i) in the thickened basement membrane of asthmatic lower...

Research paper thumbnail of Comparative Serum Hyaluronan Levels in Patients with Aspirin-Exacerbated Respiratory Disease, Asthma, and Healthy Controls

Journal of Allergy and Clinical Immunology, 2015

Research paper thumbnail of Hindlimb unloading induces a collagen isoform shift in the soleus muscle of the rat

American journal of physiology. Regulatory, integrative and comparative physiology, 2001

To determine whether hindlimb unloading (HU) alters the extracellular matrix of skeletal muscle, ... more To determine whether hindlimb unloading (HU) alters the extracellular matrix of skeletal muscle, male Sprague-Dawley rats were subjected to 0 (n = 11), 1 (n = 11), 14 (n = 13), or 28 (n = 11) days of unloading. Remodeling of the soleus and plantaris muscles was examined biochemically for collagen abundance via measurement of hydroxyproline, and the percentage of cross-sectional area of collagen was determined histologically with picrosirius red staining. Total hydroxyproline content in the soleus and plantaris muscles was unaltered by HU at any time point. However, the relative proportions of type I collagen in the soleus muscle decreased relative to control (Con) with 14 and 28 days HU (Con 68 +/- 5%; 14 days HU 53 +/- 4%; 28 days HU 53 +/- 7%). Correspondingly, type III collagen increased in soleus muscle with 14 and 28 days HU (Con 32 +/- 5%; 14 days HU 47 +/- 4%; 28 days HU 48 +/- 7%). The proportion of type I muscle fibers in soleus muscle was diminished with HU (Con 96 +/- 2%;...

Research paper thumbnail of Novel insights in mammalian catalase heme maturation: Effect of NO and thioredoxin-1

Free radical biology & medicine, Jan 4, 2015

Catalase is a tetrameric heme-containing enzyme with essential antioxidant functions in biology. ... more Catalase is a tetrameric heme-containing enzyme with essential antioxidant functions in biology. Multiple factors including nitric oxide (NO) have been shown to attenuate its activity. However, the possible impact of NO in relation to the maturation of active catalase, including its heme acquisition and tetramer formation, has not been investigated. We found that NO attenuates heme insertion into catalase in both short-term and long-term incubations. The NO inhibition in catalase heme incorporation was associated with defective oligomerization of catalase, such that inactive catalase monomers and dimers accumulated in place of the mature tetrameric enzyme. We also found that GAPDH plays a key role in mediating these NO effects on the structure and activity of catalase. Moreover, the NO sensitivity of catalase maturation could be altered up or down by manipulating the cellular expression level or activity of thioredoxin-1, a known protein-SNO denitrosylase enzyme. In a mouse model of...

Research paper thumbnail of Interleukin-2-induces development of denditric cells from cord blood CD34+ cells

Journal of leukocyte biology, 1998

Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differenti... more Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differentiation propagated from bone marrow or early thymic precursor cells with hematopoietic cytokines. In our study, we have induced growth and differentiation of DC from cord blood CD34+ cells initiated in interleukin-2 (IL-2) alone or in IL-2 + stem cell factor (SCF) + tumor necrosis factor alpha (TNF-alpha)-supplemented medium and cultured with IL-2 or IL-2 + SCF for 28-35 days. Dendritic morphology and antigenic phenotype of DC grown with IL-2 were characteristic for DC cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Growth and differentiation of DC was followed by an increase in expression of MHC II and co-stimulating molecules CD80 and CD86. We have also shown the expression of the IL-2 receptor (IL-2R) gamma-chain in CD34+ cells after 2-3 days of culture with IL-2 alone. The co-expression of the IL-2R alpha, beta, and gamma subunits in both DC cultu...

Research paper thumbnail of NO and denitrosylases regulate maturation of active catalase by influencing its heme incorporation and tetrameric structure

Research paper thumbnail of Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice

Research paper thumbnail of Renal handling of homocysteine during normal pregnancy and preeclampsia

Journal of the Society for Gynecologic Investigation, 2004

Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in pree... more Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in preeclampsia. The goal of this study was to investigate the role of the maternal kidney in the changes of plasma homocysteine during normal pregnancy and preeclampsia. Plasma and 24-hour urine samples were collected in the same women before, during (first, second, and third trimesters), and after normal pregnancy; and in a separate cross-sectional study of normal pregnant, preeclamptic and nonpregnant women and homocysteine concentrations were measured. Longitudinally, maternal plasma homocysteine decreased significantly by the first trimester compared with prepregnancy and postpartum levels (5.6 +/- 1.8 versus 6.8 +/- 0.5 and 7.4 +/- 0.4 microM, respectively, P<.05 by analysis of variance) and paralleled a significant increase in the renal clearance of homocysteine (2.9 +/- 0.4 versus 1.8 +/- 0.2 and 1.6 +/- 0.2 L/24 hours, respectively, P<.001). In addition, plasma homocysteine was significantly elevated in preeclampsia compared with normal pregnancy (4.4 +/- 0.6 versus 3.2 +/- 0.2 microM, P<.04); however, renal clearance was not different (1.2 +/- 0.1 versus 1.0 +/- 0.1 L/24 hours, P=.55). Increases in renal clearance contribute to the decrease in plasma homocysteine during normal pregnancy. However, changes in renal handling do not appear to contribute to the increase in plasma homocysteine in preeclampsia.

Research paper thumbnail of A Deficiency of Cysteine Impairs Fibrillin-1 Deposition: Implications for the Pathogenesis of Cystathionine β-Synthase Deficiency

Molecular Genetics and Metabolism, 2000

Cystathionine ␤-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pl... more Cystathionine ␤-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pleiotropic manifestations and is commonly called "homocystinuria." The features include skeletal, ocular, and vascular defects, some of which are reminiscent of those found in Marfan syndrome (MFS). Because of the spectrum of clinical effects, the pathogenesis of homocystinuria has long been thought to involve the extracellular matrix (ECM), and the condition has been classified as a heritable disorder of connective tissue. Because of the superficial similarities with MFS, we and others (Pyeritz,

Research paper thumbnail of Upregulation of smooth muscle cell collagen production by homocysteine—insight into the pathogenesis of homocystinuria

Molecular Genetics and Metabolism, 2002

Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thi... more Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thickening and collagen-rich, fibrous plaques. We previously demonstrated that homocysteine (Hcy) upregulates collagen synthesis and accumulation by arterial smooth muscle cells (SMCs) [A.

Research paper thumbnail of Pertussis toxin and genistein inhibit cell proliferation but not collagen synthesis by arterial smooth muscle cells

Research paper thumbnail of Royal academy of medicine in Ireland international conference on homocysteine metabolism from basic science to clinical medicine

Irish Journal of Medical Science, 1995

VITAMIN B 12, S-MMA AND S-HCY - A POPULATION STUDY OF MEN AND WOMEN AGED 70 YEARS OR OLDER K. Bjr... more VITAMIN B 12, S-MMA AND S-HCY - A POPULATION STUDY OF MEN AND WOMEN AGED 70 YEARS OR OLDER K. Bjrrkegren. Department of Family Medicine, Uppsala University, Uppsala, Sweden. In an industrial community with 9.300 inhabitants, in central Sweden, a ...

Research paper thumbnail of Nitric oxide alters hyaluronan deposition by airway smooth muscle cells

PLOS ONE, 2018

Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matr... more Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matrix, including changes in hyaluronan (HA) deposition. However, little is known about the factors that modulate its deposition or the potential consequences. Asthmatics with high levels of exhaled nitric oxide (NO) are characterized by greater airway reactivity and greater evidence of airway inflammation. Based on these data and our previous work we hypothesized that excessive NO promotes the pathologic production of HA by airway smooth muscle cells (SMCs). Exposure of cultured SMCs to various NO donors results in the accumulation of HA in the form of unique, cable-like structures. HA accumulates rapidly after exposure to NO and can be seen as early as one hour after NO treatment. The cable-like HA in NO-treated SMC cultures supports the binding of leukocytes. In addition, NO produced by murine macrophages (RAW cells) and airway epithelial cells also induces SMCs to produce HA cables when grown in co-culture. The modulation of HA by NO appears to be independent of soluble guanylate cyclase. Taken together, NO-induced production of leukocyte-binding HA by SMCs provides a new potential mechanism for the non-resolving airway inflammation in asthma and suggests a key role of non-immune cells in driving the chronic inflammation of the submucosa. Modulation of NO, HA and the consequent immune cell interactions may serve as potential therapeutic targets in asthma.

Research paper thumbnail of Growth hormone injections improve bone quality in OI mice

Research paper thumbnail of Characterization, Distribution and Putative Function of ADAMTSL4, an Extracellular Protein Mutated in Recessive Ectopia Lentis

Investigative Ophthalmology & Visual Science, 2010

Research paper thumbnail of Homocystetne and other thiols are non-mttogenic in balamm-replete aortic smooth muscle cells

Research paper thumbnail of TNF-stimulated gene 6 promotes formation of hyaluronan–inter-α-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness

Journal of Biological Chemistry

Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (A... more Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-␣-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptor binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological HA-HC matrix. However, the role of TSG-6 in acute airway inflammation is not well understood. Here, we hypothesized that TSG-6 is essential for the development of HA-and ozone-induced AHR. TSG-6 ؊/؊ and TSG-6 ؉/؉ mice were exposed to ozone or short-fragment HA (sHA), and AHR was assayed via flexiVent. The AHR response to sHA was evaluated in the isolated tracheal ring assay in tracheal rings from TSG-6 ؊/؊ or TSG-6 ؉/؉ , with or without the addition of exogenous TSG-6, and with or without inhibitors of Rho-associated, coiled-coil-containing protein kinase (ROCK), ERK, or PI3K. Smooth-muscle cells from mouse tracheas were assayed in vitro for signaling pathways. We found that TSG-6 deficiency protects against AHR after ozone (in vivo) or sHA (in vitro and in vivo) exposure. Moreover, TSG-6 ؊/؊ tracheal ring non-responsiveness to sHA was reversed by exogenous TSG-6 addition. sHA rapidly activated RhoA, ERK, and Akt in airway smooth-muscle cells, but only in the presence of TSG-6. Inhibition of ROCK, ERK, or PI3K/Akt blocked sHA/TSG-6-mediated AHR. In conclusion, TSG-6 is necessary for AHR in response to ozone or sHA, in part because it facilitates rapid formation of HA-HC complexes. The sHA/TSG-6 effect is mediated by RhoA, ERK, and PI3K/ Akt signaling.

Research paper thumbnail of IL-17A Recruits Rab35 to IL-17R to Mediate PKCα-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility

The Journal of Immunology

Research paper thumbnail of Hyaluronan and Nitric Oxide Collaborate As Inflammatory Mediators in Asthma

Data Revues 00916749 V131i2ss S0091674912028412, Jan 26, 2013

RATIONALE: Lipid rafts in epithelial cell membrane plays multifunctions, including components of ... more RATIONALE: Lipid rafts in epithelial cell membrane plays multifunctions, including components of immune system and important mediators in inflammatory process. But the role of cholesterol, composing lipid rafts, has not been described in the inflammatory response. The aim of this study is to investigate the effect of cholesterol depletion to inflammatory process via expression of interleukin (IL)-8 in airway epithelial cells. METHODS: The human epithelial-like lung carcinoma cell line(A 549) was treated with 0.5% methyl-b-cyclodextrin as a selective cholesterol extractor. IL-8 levels were assessed by enzyme-linked immunosorbent assay (ELISA) and rechecked after cholesterol repletion. Mitogen-activated protein kinase (MAPK) inhibitors were used to find upstream signaling pathway for IL-8 production in cholesterol-depleted cells. RESULTS: IL-8 production in cholesterol-depleted epithelial cells increased in a time-dependent manner. The maximum production of IL-8 recorded at 24 h was almost 3.5 times more than control cells. In addition, it reversed after cholesterol repletion. And IL-8 production decreased followed by pretreatment with extracellular signal-regulated kinase (ERK) inhibitor U0126, but not with JNK inhibitor II or p38 MAPK inhibitor SB202190. CONCLUSIONS: These results suggested that inflammatory responses could be increased in cholesterol-depleted cells, and it was regulated by MAPK signaling system, predominantly by ERK pathway. We concluded that lipid component in airway epithelial cells may play a role in inflammatory process.

Research paper thumbnail of Plasma homocysteine and malondialdehyde are correlated in an age- and gender-specific manner

Metabolism Clinical and Experimental, Nov 1, 2002

Homocysteine is an independent risk factor for peripheral vascular and coronary artery disease. T... more Homocysteine is an independent risk factor for peripheral vascular and coronary artery disease. The exact mechanism by which homocysteine promotes vascular dysfunction is unclear, but it is speculated to involve oxidative stress. Several studies have investigated the role of homocysteine in promoting oxidative stress and have obtained conflicting results. The age and gender of the subject populations in these studies may have influenced the outcome. Therefore, we investigated whether plasma homocysteine concentrations were correlated with plasma malondialdehyde (MDA, a marker of oxidative stress), and if the subject's age and gender affected this correlation. Plasma homocysteine and MDA were measured in 35 premenopausal women, 14 young men, 38 postmenopausal women, and 18 older men. Homocysteine was significantly higher in men than women (P <.01) and in older subjects versus younger. However, MDA was significantly greater only in the young men (P <.01). Furthermore, there was a significant correlation between homocysteine and MDA only in these young men (R(2) = 0.50, P <.01). Lastly, subjects undergoing a methionine load did not exhibit increased MDA despite significant increases in homocysteine. Since oxidative stress correlates with basal homocysteine only in young men and does not increase with acutely increased homocysteine, it is unlikely to be the result of a direct effect of homocysteine.

Research paper thumbnail of Hyaluronan and its heavy chain modification in asthma severity and experimental asthma exacerbation

The Journal of biological chemistry, Jan 24, 2015

Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has bee... more Hyaluronan (HA) is a large (>1500 kDa) polysaccharide of the extracellular matrix that has been linked to severity and inflammation in asthma. During inflammation, HA becomes covalently modified with heavy chains (HC-HA) from inter-α-inhibitor (IαI) which functions to increase its avidity for leukocytes. Our murine model of allergic pulmonary inflammation suggested that HC-HA may contribute to inflammation, adversely effecting lower airway remodeling and asthma severity. Our objective was to characterize the levels of HA and HC-HA in asthmatic subjects and to correlate these levels with asthma severity. We determined the levels and distribution of HA and HC-HA (i) from asthmatic and control lung tissue, (ii) in bronchoalveolar lavage fluid obtained from non-severe and severe asthmatics and controls and (iii) in serum and urine from atopic asthmatics after an experimental asthma exacerbation. HC-HA distribution was observed (i) in the thickened basement membrane of asthmatic lower...

Research paper thumbnail of Comparative Serum Hyaluronan Levels in Patients with Aspirin-Exacerbated Respiratory Disease, Asthma, and Healthy Controls

Journal of Allergy and Clinical Immunology, 2015

Research paper thumbnail of Hindlimb unloading induces a collagen isoform shift in the soleus muscle of the rat

American journal of physiology. Regulatory, integrative and comparative physiology, 2001

To determine whether hindlimb unloading (HU) alters the extracellular matrix of skeletal muscle, ... more To determine whether hindlimb unloading (HU) alters the extracellular matrix of skeletal muscle, male Sprague-Dawley rats were subjected to 0 (n = 11), 1 (n = 11), 14 (n = 13), or 28 (n = 11) days of unloading. Remodeling of the soleus and plantaris muscles was examined biochemically for collagen abundance via measurement of hydroxyproline, and the percentage of cross-sectional area of collagen was determined histologically with picrosirius red staining. Total hydroxyproline content in the soleus and plantaris muscles was unaltered by HU at any time point. However, the relative proportions of type I collagen in the soleus muscle decreased relative to control (Con) with 14 and 28 days HU (Con 68 +/- 5%; 14 days HU 53 +/- 4%; 28 days HU 53 +/- 7%). Correspondingly, type III collagen increased in soleus muscle with 14 and 28 days HU (Con 32 +/- 5%; 14 days HU 47 +/- 4%; 28 days HU 48 +/- 7%). The proportion of type I muscle fibers in soleus muscle was diminished with HU (Con 96 +/- 2%;...

Research paper thumbnail of Novel insights in mammalian catalase heme maturation: Effect of NO and thioredoxin-1

Free radical biology & medicine, Jan 4, 2015

Catalase is a tetrameric heme-containing enzyme with essential antioxidant functions in biology. ... more Catalase is a tetrameric heme-containing enzyme with essential antioxidant functions in biology. Multiple factors including nitric oxide (NO) have been shown to attenuate its activity. However, the possible impact of NO in relation to the maturation of active catalase, including its heme acquisition and tetramer formation, has not been investigated. We found that NO attenuates heme insertion into catalase in both short-term and long-term incubations. The NO inhibition in catalase heme incorporation was associated with defective oligomerization of catalase, such that inactive catalase monomers and dimers accumulated in place of the mature tetrameric enzyme. We also found that GAPDH plays a key role in mediating these NO effects on the structure and activity of catalase. Moreover, the NO sensitivity of catalase maturation could be altered up or down by manipulating the cellular expression level or activity of thioredoxin-1, a known protein-SNO denitrosylase enzyme. In a mouse model of...

Research paper thumbnail of Interleukin-2-induces development of denditric cells from cord blood CD34+ cells

Journal of leukocyte biology, 1998

Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differenti... more Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differentiation propagated from bone marrow or early thymic precursor cells with hematopoietic cytokines. In our study, we have induced growth and differentiation of DC from cord blood CD34+ cells initiated in interleukin-2 (IL-2) alone or in IL-2 + stem cell factor (SCF) + tumor necrosis factor alpha (TNF-alpha)-supplemented medium and cultured with IL-2 or IL-2 + SCF for 28-35 days. Dendritic morphology and antigenic phenotype of DC grown with IL-2 were characteristic for DC cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Growth and differentiation of DC was followed by an increase in expression of MHC II and co-stimulating molecules CD80 and CD86. We have also shown the expression of the IL-2 receptor (IL-2R) gamma-chain in CD34+ cells after 2-3 days of culture with IL-2 alone. The co-expression of the IL-2R alpha, beta, and gamma subunits in both DC cultu...

Research paper thumbnail of NO and denitrosylases regulate maturation of active catalase by influencing its heme incorporation and tetrameric structure

Research paper thumbnail of Hyperhomocysteinemia induced by methionine supplementation does not independently cause atherosclerosis in C57BL/6J mice

Research paper thumbnail of Renal handling of homocysteine during normal pregnancy and preeclampsia

Journal of the Society for Gynecologic Investigation, 2004

Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in pree... more Maternal plasma homocysteine decreases in normal pregnancy and is significantly increased in preeclampsia. The goal of this study was to investigate the role of the maternal kidney in the changes of plasma homocysteine during normal pregnancy and preeclampsia. Plasma and 24-hour urine samples were collected in the same women before, during (first, second, and third trimesters), and after normal pregnancy; and in a separate cross-sectional study of normal pregnant, preeclamptic and nonpregnant women and homocysteine concentrations were measured. Longitudinally, maternal plasma homocysteine decreased significantly by the first trimester compared with prepregnancy and postpartum levels (5.6 +/- 1.8 versus 6.8 +/- 0.5 and 7.4 +/- 0.4 microM, respectively, P<.05 by analysis of variance) and paralleled a significant increase in the renal clearance of homocysteine (2.9 +/- 0.4 versus 1.8 +/- 0.2 and 1.6 +/- 0.2 L/24 hours, respectively, P<.001). In addition, plasma homocysteine was significantly elevated in preeclampsia compared with normal pregnancy (4.4 +/- 0.6 versus 3.2 +/- 0.2 microM, P<.04); however, renal clearance was not different (1.2 +/- 0.1 versus 1.0 +/- 0.1 L/24 hours, P=.55). Increases in renal clearance contribute to the decrease in plasma homocysteine during normal pregnancy. However, changes in renal handling do not appear to contribute to the increase in plasma homocysteine in preeclampsia.

Research paper thumbnail of A Deficiency of Cysteine Impairs Fibrillin-1 Deposition: Implications for the Pathogenesis of Cystathionine β-Synthase Deficiency

Molecular Genetics and Metabolism, 2000

Cystathionine ␤-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pl... more Cystathionine ␤-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pleiotropic manifestations and is commonly called "homocystinuria." The features include skeletal, ocular, and vascular defects, some of which are reminiscent of those found in Marfan syndrome (MFS). Because of the spectrum of clinical effects, the pathogenesis of homocystinuria has long been thought to involve the extracellular matrix (ECM), and the condition has been classified as a heritable disorder of connective tissue. Because of the superficial similarities with MFS, we and others (Pyeritz,

Research paper thumbnail of Upregulation of smooth muscle cell collagen production by homocysteine—insight into the pathogenesis of homocystinuria

Molecular Genetics and Metabolism, 2002

Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thi... more Patients with untreated homocystinuria have widespread premature atherosclerosis with intimal thickening and collagen-rich, fibrous plaques. We previously demonstrated that homocysteine (Hcy) upregulates collagen synthesis and accumulation by arterial smooth muscle cells (SMCs) [A.