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Papers by Jo-Dee Lattimore

Heart, Lung and Circulation

PROTEOMICS – CLINICAL APPLICATIONS, 2008

There is currently no blood-based test that can rapidly and objectively distinguish between chest... more There is currently no blood-based test that can rapidly and objectively distinguish between chest pain which is initiated by increased myocardial oxygen demand (stable angina pectoris (SAP)) and chest pain initiated due to decreased coronary blood flow (unstable angina pectoris (UAP)). Since leukocytes play an active role in the progression of coronary artery disease (CAD), we hypothesize these can provide novel markers of SAP and UAP. Here we use a microarray of 82 cluster of differentiation (CD) antibodies (plus controls) to selectively immobilize peripheral blood mononuclear cells. We find that the pattern of leukocyte immobilization from patients with CAD significantly differs from healthy donors. Within the CAD group, 15 SAP patients exhibited significant (p<0.05) changes in 8 of 82 CD antibody spots compared to 19 age-matched healthy blood donors. An additional ten CD antigens differed between healthy donors and patients with UAP (p<0.05). Furthermore, seven CD antibody spots are significantly different between SAP and UAP patients. These preliminary data suggest it is now appropriate to undertake a larger clinical trial to test the hypothesis that these antibody microarrays can monitor the progression from SAP to UAP.

New England Journal of Medicine, 2011

Mammals have oxygen-sensing mechanisms that help them adapt quickly to hypoxia by increasing resp... more Mammals have oxygen-sensing mechanisms that help them adapt quickly to hypoxia by increasing respiration, blood flow, and survival responses. If an inadequate supply of oxygen persists, additional mechanisms attempt to restore oxygenation or help the body adapt to hypoxia. 1 These other mechanisms rely on oxygen-sensing prolyl hydroxylases (PHDs), which hydroxylate prolines in the alpha subunit of the hypoxia-inducible transcription factor (HIF). This transcription factor is a heterodimer with two subunits: HIF-1α or HIF-2α and HIF-1β (or aryl hydrocarbon receptor nuclear translocator [ARNT] protein). HIF-1α is ubiquitous, whereas HIF-2α is restricted to certain tissues. 1 In this review, we show the ways in which the PHD-HIF system affects inflammatory processes. We discuss the regulation of immune responses by hypoxia-induced signaling, outline molecular aspects of the cross-talk between hypoxia and inflammation, and illustrate the link between hypoxia and inflammation in inflammatory bowel disease, certain cancers, and infections. HYPOXIA-INDUCED INFLAMMATION The concept that hypoxia can induce inflammation has gained general acceptance from studies of the hypoxia signaling pathway. In persons with mountain sickness, for example, levels of circulating proinflammatory cytokines increase, and leakage of fluid ("vascular leakage") causes pulmonary or cerebral edema. 1-3 Increased serum levels of interleukin-6, the interleukin-6 receptor, and C-reactive protein-all markers of inflammation-were increased in healthy volunteers who spent 3 nights at an elevation higher than 3400 m. 4 At 8400 m, healthy climbers ascending Mount Everest had severe hypoxemia (partial pressure of arterial oxygen [PaO 2 ], 25 mm Hg). Alveolar-arterial oxygen differences were elevated in these climbers, a finding that is consistent with subclinical high-altitude pulmonary edema. 3 Moreover, vascular leakage, accumulations of inflammatory cells in multiple organs, and elevated serum levels of cytokines occur in mice after short-term exposure to low oxygen concentrations. 5-9 The development of inflammation in response to hypoxia is clinically relevant. Ischemia in organ grafts increases the risk of inflammation and graft failure or rejection. 10 In patients undergoing kidney transplantation, the renal expression of toll-like receptor (TLR) 4-an extracellular receptor for bacterial lipopolysaccharide-was shown to correlate with the degree of ischemic injury. In this study, donor kidneys with a loss-of-function TLR4 allele,

International Journal of Cardiology, 2008

Background: Obstructive sleep apnoea (OSA) is associated with pulmonary hypertension, however nei... more Background: Obstructive sleep apnoea (OSA) is associated with pulmonary hypertension, however neither the pathogenesis of pulmonary vascular disease nor the effect of successful treatment of OSA on pulmonary vascular physiology has been characterised. Methods: Seven subjects aged 52 (range 36-63) years with moderate to severe obstructive sleep apnoea (apnoea-hypopnoea index N 15/h) had detailed pulmonary vascular reactivity studies, before and after 3 months of successful treatment with nasal continuous positive airways pressure (CPAP). On both occasions, we measured pulmonary pressure, flow velocity, flow and resistance, at baseline and in response to acetylcholine (an endothelium-dependent dilator), sodium nitroprusside (an endothelium-independent dilator), L-NMMA (an antagonist of nitric oxide synthesis) and L-Arginine (the substrate of nitric oxide). Results: At baseline, pulmonary flow increased in response to acetylcholine and nitroprusside and fell in response to L-NMMA. Following CPAP treatment, the decrease in flow to L-NMMA was significantly greater (to 62 ± 6% of control value vs 85 ± 6% of pre-treatment; p = 0.01), consistent with enhanced basal release of nitric oxide. The acetylcholine response tended to be greater after treatment (174 ± 26% of control vs 147 ± 12% of pre-CPAP, p = 0.22), however the nitroprusside response was unchanged. Conclusion: Successful treatment of obstructive sleep apnoeic episodes in sleep results in enhanced nitric oxide release by the pulmonary microvascular circulation.

Heart, Lung and Circulation, 2003

In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attribute... more In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy. Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 +/- 3 weeks of uncomplicated pregnancy and in the same women 7 +/- 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls. Resting forearm vascular resistance was similar during pregnancy (33 +/- 16 arbitrary units (AU)), after pregnancy (31 +/- 10 AU) and in controls (41 +/- 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 microg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 microg/min) were similar in all groups. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (16 micromol/min) produced similar increases in vascular resistance in pregnant women (38 +/- 17 AU), after pregnancy (36 +/- 14 AU) and in control subjects (42 +/- 8 AU, P = NS). These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.

Heart, Lung and Circulation, 2003

Heart, Lung and Circulation, Volume 12, Issue 2, Pages A44, 2003, Authors:Jo-Dee L. Lattimore; Ia... more Heart, Lung and Circulation, Volume 12, Issue 2, Pages A44, 2003, Authors:Jo-Dee L. Lattimore; Ian Wilcox; Kris McGrath; Shirley Nakhla; David S. Celermajer; Alison K. Death. Journal Home. Register or Login: Password: Auto-Login [Reminder]. ...

Atherosclerosis, 2005

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of hypoxia and is associate... more Obstructive sleep apnea (OSA) is characterized by repetitive episodes of hypoxia and is associated with an increase in cardiovascular disease. We, therefore, investigated the effect of repetitive hypoxia on two key early events in atherogenesis; lipid loading in foam cells and monocyte adhesion to endothelial cells. Human macrophages were loaded with acetylated low-density lipoproteins. During lipid loading, the cells were exposed to 30 min cycles of 2%/21% oxygen or control (room air, 5% CO 2 incubator). Human umbilical vein endothelial cells (HUVECs) were also exposed to 30 min cycles of repetitive hypoxia or control conditions and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were measured by ELISA. Repetitive hypoxia increased cholesteryl ester uptake by macrophages (127 ± 5% compared to controls; p = 0.003). By contrast, monocyte adhesion to HUVECs and cell adhesion molecule expression were unchanged by exposure to repetitive hypoxia, compared to controls (p > 0.1). Repetitive hypoxia, at levels relevant to tissues such as the arterial wall, enhances lipid uptake into human macrophages. This may contribute to accelerated atherosclerosis in OSA patients.

Cleveland Clinic Journal of Medicine, 2008

New England Journal of Medicine, 2006

Heart, Lung and Circulation

PROTEOMICS – CLINICAL APPLICATIONS, 2008

There is currently no blood-based test that can rapidly and objectively distinguish between chest... more There is currently no blood-based test that can rapidly and objectively distinguish between chest pain which is initiated by increased myocardial oxygen demand (stable angina pectoris (SAP)) and chest pain initiated due to decreased coronary blood flow (unstable angina pectoris (UAP)). Since leukocytes play an active role in the progression of coronary artery disease (CAD), we hypothesize these can provide novel markers of SAP and UAP. Here we use a microarray of 82 cluster of differentiation (CD) antibodies (plus controls) to selectively immobilize peripheral blood mononuclear cells. We find that the pattern of leukocyte immobilization from patients with CAD significantly differs from healthy donors. Within the CAD group, 15 SAP patients exhibited significant (p<0.05) changes in 8 of 82 CD antibody spots compared to 19 age-matched healthy blood donors. An additional ten CD antigens differed between healthy donors and patients with UAP (p<0.05). Furthermore, seven CD antibody spots are significantly different between SAP and UAP patients. These preliminary data suggest it is now appropriate to undertake a larger clinical trial to test the hypothesis that these antibody microarrays can monitor the progression from SAP to UAP.

New England Journal of Medicine, 2011

Mammals have oxygen-sensing mechanisms that help them adapt quickly to hypoxia by increasing resp... more Mammals have oxygen-sensing mechanisms that help them adapt quickly to hypoxia by increasing respiration, blood flow, and survival responses. If an inadequate supply of oxygen persists, additional mechanisms attempt to restore oxygenation or help the body adapt to hypoxia. 1 These other mechanisms rely on oxygen-sensing prolyl hydroxylases (PHDs), which hydroxylate prolines in the alpha subunit of the hypoxia-inducible transcription factor (HIF). This transcription factor is a heterodimer with two subunits: HIF-1α or HIF-2α and HIF-1β (or aryl hydrocarbon receptor nuclear translocator [ARNT] protein). HIF-1α is ubiquitous, whereas HIF-2α is restricted to certain tissues. 1 In this review, we show the ways in which the PHD-HIF system affects inflammatory processes. We discuss the regulation of immune responses by hypoxia-induced signaling, outline molecular aspects of the cross-talk between hypoxia and inflammation, and illustrate the link between hypoxia and inflammation in inflammatory bowel disease, certain cancers, and infections. HYPOXIA-INDUCED INFLAMMATION The concept that hypoxia can induce inflammation has gained general acceptance from studies of the hypoxia signaling pathway. In persons with mountain sickness, for example, levels of circulating proinflammatory cytokines increase, and leakage of fluid ("vascular leakage") causes pulmonary or cerebral edema. 1-3 Increased serum levels of interleukin-6, the interleukin-6 receptor, and C-reactive protein-all markers of inflammation-were increased in healthy volunteers who spent 3 nights at an elevation higher than 3400 m. 4 At 8400 m, healthy climbers ascending Mount Everest had severe hypoxemia (partial pressure of arterial oxygen [PaO 2 ], 25 mm Hg). Alveolar-arterial oxygen differences were elevated in these climbers, a finding that is consistent with subclinical high-altitude pulmonary edema. 3 Moreover, vascular leakage, accumulations of inflammatory cells in multiple organs, and elevated serum levels of cytokines occur in mice after short-term exposure to low oxygen concentrations. 5-9 The development of inflammation in response to hypoxia is clinically relevant. Ischemia in organ grafts increases the risk of inflammation and graft failure or rejection. 10 In patients undergoing kidney transplantation, the renal expression of toll-like receptor (TLR) 4-an extracellular receptor for bacterial lipopolysaccharide-was shown to correlate with the degree of ischemic injury. In this study, donor kidneys with a loss-of-function TLR4 allele,

International Journal of Cardiology, 2008

Background: Obstructive sleep apnoea (OSA) is associated with pulmonary hypertension, however nei... more Background: Obstructive sleep apnoea (OSA) is associated with pulmonary hypertension, however neither the pathogenesis of pulmonary vascular disease nor the effect of successful treatment of OSA on pulmonary vascular physiology has been characterised. Methods: Seven subjects aged 52 (range 36-63) years with moderate to severe obstructive sleep apnoea (apnoea-hypopnoea index N 15/h) had detailed pulmonary vascular reactivity studies, before and after 3 months of successful treatment with nasal continuous positive airways pressure (CPAP). On both occasions, we measured pulmonary pressure, flow velocity, flow and resistance, at baseline and in response to acetylcholine (an endothelium-dependent dilator), sodium nitroprusside (an endothelium-independent dilator), L-NMMA (an antagonist of nitric oxide synthesis) and L-Arginine (the substrate of nitric oxide). Results: At baseline, pulmonary flow increased in response to acetylcholine and nitroprusside and fell in response to L-NMMA. Following CPAP treatment, the decrease in flow to L-NMMA was significantly greater (to 62 ± 6% of control value vs 85 ± 6% of pre-treatment; p = 0.01), consistent with enhanced basal release of nitric oxide. The acetylcholine response tended to be greater after treatment (174 ± 26% of control vs 147 ± 12% of pre-CPAP, p = 0.22), however the nitroprusside response was unchanged. Conclusion: Successful treatment of obstructive sleep apnoeic episodes in sleep results in enhanced nitric oxide release by the pulmonary microvascular circulation.

Heart, Lung and Circulation, 2003

In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attribute... more In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy. Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 +/- 3 weeks of uncomplicated pregnancy and in the same women 7 +/- 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls. Resting forearm vascular resistance was similar during pregnancy (33 +/- 16 arbitrary units (AU)), after pregnancy (31 +/- 10 AU) and in controls (41 +/- 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 microg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 microg/min) were similar in all groups. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (16 micromol/min) produced similar increases in vascular resistance in pregnant women (38 +/- 17 AU), after pregnancy (36 +/- 14 AU) and in control subjects (42 +/- 8 AU, P = NS). These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.

Heart, Lung and Circulation, 2003

Heart, Lung and Circulation, Volume 12, Issue 2, Pages A44, 2003, Authors:Jo-Dee L. Lattimore; Ia... more Heart, Lung and Circulation, Volume 12, Issue 2, Pages A44, 2003, Authors:Jo-Dee L. Lattimore; Ian Wilcox; Kris McGrath; Shirley Nakhla; David S. Celermajer; Alison K. Death. Journal Home. Register or Login: Password: Auto-Login [Reminder]. ...

Atherosclerosis, 2005

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of hypoxia and is associate... more Obstructive sleep apnea (OSA) is characterized by repetitive episodes of hypoxia and is associated with an increase in cardiovascular disease. We, therefore, investigated the effect of repetitive hypoxia on two key early events in atherogenesis; lipid loading in foam cells and monocyte adhesion to endothelial cells. Human macrophages were loaded with acetylated low-density lipoproteins. During lipid loading, the cells were exposed to 30 min cycles of 2%/21% oxygen or control (room air, 5% CO 2 incubator). Human umbilical vein endothelial cells (HUVECs) were also exposed to 30 min cycles of repetitive hypoxia or control conditions and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were measured by ELISA. Repetitive hypoxia increased cholesteryl ester uptake by macrophages (127 ± 5% compared to controls; p = 0.003). By contrast, monocyte adhesion to HUVECs and cell adhesion molecule expression were unchanged by exposure to repetitive hypoxia, compared to controls (p > 0.1). Repetitive hypoxia, at levels relevant to tissues such as the arterial wall, enhances lipid uptake into human macrophages. This may contribute to accelerated atherosclerosis in OSA patients.

Cleveland Clinic Journal of Medicine, 2008

New England Journal of Medicine, 2006