anne sturrock - Academia.edu (original) (raw)

Papers by anne sturrock

This article cites 29 articles, 15 of which can be accessed free

Persistent hypoxia can cause pulmonary arterial hypertension (PAH) that may be associated with si... more Persistent hypoxia can cause pulmonary arterial hypertension (PAH) that may be associated with significant remodeling of the pulmonary arteries, including smooth muscle cell proliferation and hypertrophy. We previously demonstrated that the NADPH oxidase homologue NOX4 mediates human pulmonary artery smooth muscle cell (HPASMC) proliferation by transforming growth factorβ1 (TGF-β1). We now show that hypoxia increases HPASMC proliferation in vitro, accompanied by increased ROS generation and NOX4 gene expression, and inhibited by antioxidants, the flavoenzyme inhibitor diphenyleneiodonium (DPI) and NOX4 gene silencing. HPASMC proliferation and NOX4 expression are also observed when media from hypoxic HPASMC is added to HPASMC grown in normoxic conditions, suggesting autocrine stimulation. TGF-β1 and insulinlike growth factor binding protein-3 (IGFBP-3) are both increased in the media of hypoxic HPASMC, and increased IGFBP-3 gene expression is noted in hypoxic HPASMC. Treatment with a...

at http://www.the-aps.org/. Society, 9650 Rockville Pike, Bethesda MD 20814-3991. . ISSN: 1040-06... more at http://www.the-aps.org/. Society, 9650 Rockville Pike, Bethesda MD 20814-3991. . ISSN: 1040-0605, ESSN: 1522-1504. Visit our website components of the respiratory system. It is published 12 times a year (monthly) by the American Physiological the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and publishes original research covering American Journal of Physiology Lung Cellular and Molecular Physiology by gest on July 0, 2016 http://ajpphysiology.org/ D ow nladed fom

Thelater stages ofinfection bytheLymedisease pathogen, Borrelia burgdorferi, are characterized by... more Thelater stages ofinfection bytheLymedisease pathogen, Borrelia burgdorferi, are characterized bythe persistence oftheorganism inindividuals possessing astrong anti-Borrelia immuneresponse.Thissuggests that theorganism issequestered inatissue protected fromtheimmunesystemofthehost orthere isa reservoir of theorganism residing within thecellsofthehost. Inthis report, theability ofB.burgdorfieri togainentrance into humanumbilical veinendothelial cells was explored asa modelforinvasion. Incubation ofB.burgdorferi withhumanumbilical veinendothelial cells atratios ranging from200:1 to5,000:1 resulted intheintracellular localization of10to25% ofB.burgdor fieri in24h. Theintracellular location ofthespirochetes was demonstrated bytheincorporation ofradiolabeled B.burgdorferi into atrypsin-resistant compartment andwas confirmed bydouble-immunofluorescence staining whichdifferentiated intracellular fromextracellular organisms. Actin-containing microfflaments were required fortheintracellular ...

Sturrock, Anne, Barbara Cahill, Kimberly Norman, Thomas P. Huecksteadt, Kenneth Hill, Karl Sander... more Sturrock, Anne, Barbara Cahill, Kimberly Norman, Thomas P. Huecksteadt, Kenneth Hill, Karl Sanders, S. V. Karwande, James C. Stringham, David A. Bull, Martin Gleich, Thomas P. Kennedy, and John R. Hoidal. Transforming growth factor1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 290: L661–L673, 2006. First published October 14, 2005; doi:10.1152/ajplung.00269.2005.—Transforming growth factor1 (TGF1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving ...

American journal of physiology. Lung cellular and molecular physiology, 2006

Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, b... more Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-beta1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF-beta1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF-beta1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving Smad 2/3 but not mitogen-activated protein (MAP) kinases. TGF-beta1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase flavoprotein inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF-beta1, Nox4 was present in freshly cultured cells but progressively lost with each passage in culture, paralleling a decrease in ROS production by HPASMC over time. At a later time...

Physiological Reports

SARS‐CoV‐2 uptake by lung epithelial cells is a critical step in the pathogenesis of COVID‐19. Vi... more SARS‐CoV‐2 uptake by lung epithelial cells is a critical step in the pathogenesis of COVID‐19. Viral entry is dependent on the binding of the viral spike protein to the angiotensin converting enzyme II protein (ACE2) on the host cell surface, followed by proteolytic cleavage by a host serine protease such as TMPRSS2. Infection of alveolar epithelial cells (AEC) in the distal lung is a key feature in progression to the acute respiratory distress syndrome (ARDS). We hypothesized that AEC expression of ACE2 is induced by hypoxia. In a murine model of hypoxic stress (12% FiO2), the total lung Ace2 mRNA and protein expression was significantly increased after 24 hours in hypoxia compared to normoxia (21% FiO2). In experiments with primary murine type II AEC, we found that exposure to hypoxia either in vivo (prior to isolation) or in vitro resulted in greatly increased AEC expression of both Ace2 (mRNA and protein) and of Tmprss2. However, when isolated type II AEC were maintained in culture over 5 days, with loss of type II cell characteristics and induction of type I cell features, Ace2 expression was greatly reduced, suggesting that this expression was a feature of only this subset of AEC. Finally, in primary human small airway epithelial cells (SAEC), ACE2 mRNA and protein expression were also induced by hypoxia, as was binding to purified spike protein. Hypoxia‐induced increase in ACE2 expression in type II AEC may provide an explanation of the extended temporal course of human patients who develop ARDS in COVID‐19.

Journal of Environmental Science and Health, Part A

Abstract In vitro studies are a first step toward understanding the biological effects of combust... more Abstract In vitro studies are a first step toward understanding the biological effects of combustion-derived particulate matter (cdPM). A vast majority of studies expose cells to cdPM suspensions, which requires a method to collect cdPM and suspend it in an aqueous media. The consequences of different particle collection methods on particle physiochemical properties and resulting biological responses are not fully understood. This study investigated the effect of two common approaches (collection on a filter and a cold plate) and one relatively new (direct bubbling in DI water) approach to particle collection. The three approaches yielded cdPM with differences in particle size distribution, surface area, composition, and oxidative potential. The directly bubbled sample retained the smallest sized particles and the bimodal distribution observed in the gas-phase. The bubbled sample contained ∼50% of its mass as dissolved species and lower molecular weight compounds, not found in the other two samples. These differences in the cdPM properties affected the biological responses in THP-1 cells. The bubbled sample showed greater oxidative potential and cellular reactive oxygen species. The scraped sample induced the greatest TNFα secretion. These findings have implications for in vitro studies of air pollution and for efforts to better understand the underlying mechanisms.

American Journal of Physiology-Cell Physiology

The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in malignancies fr... more The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in malignancies from enhanced activity of inhibitor of NF-κB (IκB) kinase, with accelerated IκBα degradation. We studied whether redox signaling might stimulate these events. Cultured melanoma cells generated superoxide anions (O[Formula: see text]) without serum stimulation. O[Formula: see text]generation was reduced by the NAD(P)H:quinone oxidoreductase (NQO) inhibitor dicumarol and the quinone analog capsaicin, suggesting that electron transfer from NQO through a quinone-mediated pathway may be an important source of endogenous reactive oxygen species (ROS) in tumor cells. Treatment of malignant melanoma cells with the H2O2 scavenger catalase, the sulfhydryl donor N-acetylcysteine, the glutathione peroxidase mimetic ebselen, or dicumarol decreased NF-κB activation. Catalase, N-acetylcysteine, ebselen, dicumarol, and capsaicin also inhibited growth of melanoma and other malignant cell lines. These resul...

The Journal of Immunology

Pulmonary innate immune responses involve a highly regulated multicellular network to defend the ... more Pulmonary innate immune responses involve a highly regulated multicellular network to defend the enormous surface area of the lung. Disruption of these responses renders the host susceptible to pneumonia. Alveolar epithelial cells (AEC) are a critical source of innate immune molecules such as GM-CSF, which determine the functional maturation of alveolar macrophages. In many pulmonary diseases, heterogeneous ventilation leads to regional hypoxia in the lung. The effect of hypoxia on AEC innate immune function is unknown. We now report that exposure of primary murine AEC to hypoxia (1% oxygen) for 24 h results in significant suppression of key innate immune molecules, including GM-CSF, CCL2, and IL-6. This exposure did not cause toxicity but did induce stabilization of hypoxia-inducible factor 1α protein (HIF-1α) and shift to glycolytic metabolism. Focusing on GM-CSF, we found that hypoxia greatly decreased the rate of GM-CSF transcription. Hypoxia both decreased NF-κB signaling in AEC and induced chromosomal changes, resulting in decreased accessibility in the GM-CSF proximal promoter of target sequences for NF-κB binding. In mice exposed to hypoxia in vivo (12% oxygen for 2 d), lung GM-CSF protein expression was reduced. In vivo phagocytosis of fluorescent beads by alveolar macrophages was also suppressed, but this effect was reversed by treatment with GM-CSF. These studies suggest that in critically ill patients, local hypoxia may contribute to the susceptibility of poorly ventilated lung units to infection through complementary effects on several pathways, reducing AEC expression of GM-CSF and other key innate immune molecules.

Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering, Jan 21, 2018

The physicochemical properties of combustion particles that promote lung toxicity are not fully u... more The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1). Particles were generated from controlled combustion of two simple biofuel/diesel surrogates (methyl decanoate and dodecane/biofuel-blended diesel (BD), and butanol and dodecane/alcohol-blended diesel (AD)) and compared to a widely studied reference diesel (RD) particle (NIST SRM2975/RD). BD, AD, and RD particles exhibited differences in size, surface area, extractable chemical ...

American Journal of Physiology Lung Cellular and Molecular Physiology, 2007

American Journal of Physiology Lung Cellular and Molecular Physiology, 2002

A54. ALVEOLAR GENE EXPRESSION REGULATION: TRANSCRIPTION AND GROWTH FACTORS, 2009

COPD Research and Practice, 2015

Background: Air pollution is associated with adverse health effects in individuals with chronic o... more Background: Air pollution is associated with adverse health effects in individuals with chronic obstructive pulmonary disease (COPD). It is uncertain if and how individuals with COPD differ from former smokers without airflow obstruction in their response to naturally occurring episodes of particulate air pollution. We hypothesized that episodic temperature inversions with high particulate matter (PM) air pollution during the winter would be associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with COPD compared to controls. Methods: We conducted a panel study of former smokers, 16 with moderate-to-severe COPD and 12 without airflow obstruction as controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms during periods of low and high PM 2.5 (PM < 2.5 microns in diameter). We compared differences between pollution and clean air days within the COPD and control groups using linear mixed effect models. Results: High PM 2.5 levels were associated with increased EBC NOx in participants with COPD (mean ratio 3.16, p = 0.007), but not in controls (mean ratio 0.49, p = 0.23, difference between groups p = 0.01). Respiratory symptoms significantly increased on pollution days in COPD participants but not in controls. We did not detect a difference in pulmonary function or EBC 8-isoprostane. Conclusions: Former smokers with COPD have a distinctive response to particulate air pollution episodes compared to former smokers without airflow obstruction, with increased airway inflammation and respiratory symptoms.

International journal of environmental research and public health, Jan 12, 2015

This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt ... more This study aimed to determine if naturally occurring episodes of ozone air pollution in the Salt Lake Valley in Utah, USA, during the summer are associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with chronic obstructive pulmonary disease (COPD) compared to controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms in 11 former smokers with moderate-to-severe COPD and nine former smokers without airflow obstruction during periods of low and high ozone air pollution. High ozone levels were associated with increased NOx in EBC in both COPD (8.7 (±8.5) vs. 28.6 (±17.6) μmol/L on clean air vs. pollution days, respectively, p < 0.01) and control participants (7.6 (±16.5) vs. 28.5 (±15.6) μmol/L on clean air vs. pollution days, respectively, p = 0.02). There was no difference in pollution effect between COPD...

Molecular Biology of the Lung, 1999

Proteinases play a central role in the degradation of proteins by hydrolyzing peptide bonds. Orig... more Proteinases play a central role in the degradation of proteins by hydrolyzing peptide bonds. Originally thought to fulfill primarily digestive functions, it now is believed that these enzymes are the principal regulators of a multitude of crucial and diverse physiologic processes and have a central role in pathologic tissue destruction of many organs. Their role in tissue destruction has been investigated in the greatest detail in the lungs, especially in relationship to the pathogenesis of emphysema. Recent investigations suggest prominent roles for proteinases in growth and development and in intracellular signaling.