Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction

Ali, Mir H.; Schlidt, Scott A.; Chandel, Navdeep S.; Hynes, Karen L.; Schumacker, Paul T.; Gewertz, Bruce L.

doi:10.1152/ajplung.1999.277.5.l1057

Cited by 155 publications

(132 citation statements)

References 32 publications

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“…In addition, proinflammatory cytokines and chemokines directly induce changes in vascular permeability and thrombogenicity (22,23), processes implicated in the pathogenesis of pulmonary hypertension. These cytokines were also reported to promote proliferation and migration of VSMC in vitro (18,19), and disruption of the CCR2 chemokine receptor gene decreased vascular remodeling in a model of atherosclerosis in vivo (24).…”

Section: Discussionmentioning

confidence: 99%

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Minamino

Christou

Hsieh

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

352

243

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Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor-␣ signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.A cute hypoxia in the lung causes arteriolar vasoconstriction whereas prolonged hypoxia promotes proliferation and migration of vascular smooth muscle cells (VSMC) and extracellular matrix deposition in the arterial wall, a process known as vascular remodeling (1). These abnormalities are characteristic of pulmonary hypertension (2). Several clinical conditions characterized by lung inflammation have been linked to the development of chronic pulmonary hypertension (3). Interestingly, perivascular inflammatory cell infiltration as well as increased serum levels of proinflammatory cytokines, such as IL-1␤ and IL-6, have been reported in clinical cases of primary pulmonary hypertension (4, 5). However, little attention has been given up to now to the role of pulmonary inflammation in the pathogenesis of pulmonary hypertension induced by hypoxia.Heme oxygenase (HO; EC 1.14.99.3) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which is then converted to bilirubin by biliverdin reductase. Three isoforms of HO have been identified: the inducible HO-1 and the constitutively expressed HO-2 and HO-3 (6, 7). Our previous in vitro data suggest that CO released by HO-1 confers protection against vasoconstriction and vascular remodeling induced by hypoxia (8 -10). More recently, Soares et al. have suggested antiinflammatory properties of HO-1 in a cardiac transplantation model, although the molecular mechanisms have not been fully elucidated (11). Our recent in vivo data using an HO-1 null mouse model suggest that HO-1 plays a central role in protecting the right ventricle from hypoxic pulmonary pressure-induced injury (12).In the present study, we established transgenic mice that overexpress HO-1 in the lung and exposed them to hypoxia to investigate the effects of HO-1 activity on the developmen...

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Section: Discussionmentioning

confidence: 99%

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Minamino

Christou

Hsieh

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

352

243

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“…ECs are able to secrete IL-6 upon stimulation with cytokines (44,45), endotoxin (46), or endothelin-1 (47). ECs exposed to IL-6 may trigger inflammatory responses, including the increase of endothelial permeability (48). Shear flow-induced STAT3 inactivation may attenuate the IL-6-triggered responses.…”

Section: Discussionmentioning

confidence: 99%

Shear Flow Attenuates Serum-induced STAT3 Activation in Endothelial Cells

Hsieh

Chao

Wang

2003

Journal of Biological Chemistry

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ERK1/2 is involved in shear stress-and cyclic strain-induced early growth response-1 expression (5, 6). We have shown that genes such as monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule (ICAM-1), and c-fos can be induced by hemodynamic forces (7-9). The induction of these genes appears to be a redox-sensitive mechanism because an increased reactive oxygen species is required for this gene induction (7-9). Recent studies indicate that ECs under conditions of shear flow inhibit tumor necrosis factor-and H 2 O 2 -induced responses (10 -12). A recent study (13) has nicely demonstrated an induction of antioxidant response element-mediated genes in ECs exposed to laminar flow. Furthermore, shear flow has been shown to inhibit endothelial proliferation via the induction of growth arrest proteins GADD45 and p21, as well as a decrease in phosphorylation of Rb protein (14). Thus, laminar shear flow appears to play an essential role by protecting ECs from inflammatory responses and endothelial proliferation. However, the detailed mechanisms involved in this shear flowinduced protection remain unclear.Signal transducers and activators of transcriptions (STAT) are a family of functionally related proteins that play key roles in a variety of biological activities. Among these STATs, STAT3 is preferentially activated by interleukin-6 (IL-6) or other related cytokines and is required for gp130-mediated cell-survival signals (15,16). STAT3 has been intensively studied for its role in cell growth, differentiation, apoptosis, transformation, inflammation, and immune response. STAT3 is activated by tyrosine phosphorylation at a single site (Tyr-705) and by serine phosphorylation at 727 (Ser-727). Tyrosine phosphorylation of STAT3 in response to cytokine stimulation is mediated by a Janus kinase, and Src family members have been widely studied (17)(18)(19). Tyrosine phosphorylation is required for STAT3 dimerization, nuclear translocation, and DNA binding. For phosphorylation at Ser-727, there is still controversy in identifying the serine kinases. Activation of kinases, including ERK, JNK, and P38, leading to serine phosphorylation in STAT3 has been documented (16). Ser-727 phosphorylation is involved in STAT3 transcriptional activation. However, there is evidence for a negative role for serine phosphorylation. It has been shown that Ser-727 phosphorylation negatively modulates tyrosine phosphorylation (16,20,21). In addition to this cytokine-induced STAT activation, the receptor protein-tyrosine kinase-mediated activation of STAT remains elusive. Recent studies suggest that STAT3 in ECs can be activated by growth factors such as vascular endothelial growth factor (22), basic fibroblast growth factor (23), granulocyte-macrophase

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“…37 Briefly, The db/db and db/ϩ macrophages were cultured in RPMI 1640 medium containing 0.1% fetal bovine serum and 5.5 or 25 mmol/L glucose, with or without 100 nmol/L 14S,21R-diHDHA, for 3 days. Medium was changed every day.…”

Section: Reactive Oxygen Species Generation Analysis In Macrophagesmentioning

confidence: 99%

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

Tian

Lü

Shah

et al. 2011

The American Journal of Pathology

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Impaired macrophage functions imposed by diabetic complications and the suppressed formation of 14S, 2 1 R -d i h y d r o x y d o c o s a -4 Z , 7Z , 1 0 Z , 1 2 E , 1 6 Z , 19Z-hexaenoic acid (14S,21R-diHDHA) in wounds contribute significantly to deficient wound healing in diabetics, but how are macrophage functions and 14S,21R-diHDHA formation associated? We studied 14S,21R-diHDHA generation from macrophages using liquid chromatography/mass spectrometry. The role in macrophage-mediated wound healing functions was determined using a murine splinted excisional wound healing model and in vitro assays. 14S,21R-diHDHA acts as a macrophage-generated autacoid, and its attenuated formation in macrophages of diabetic db/db mice was accompanied by impairment of macrophage prohealing functions. 14S,21R-diHDHA restored db/db macrophage-impaired prohealing functions by promoting wound re-epithelialization, formulation of granulation tissue, and vascularization. Additionally, 12/15-lipoxygenase-deficient macrophages, which are unable to produce 14S,21R-diHDHA, exhibited impaired prohealing functions, which also were restored by 14S,21R-diHDHA treatment. The molecular mechanism for 14S,21R-diHDHA-induced recovery of impaired prohealing functions of db/db macrophages involves enhancing their secretion of vascular endothelial growth factor and platelet-derived growth factor BB, decreasing hyperglycemia-induced generation of reactive oxygen species, and increasing IL-10 expression under inflammatory stimulation. Taken together, these results indicate that deficiency of 14S,21R-diHDHA formation by diabetic macrophages contributes to their impaired prohealing functions. Our findings provide mechanistic insights into wound healing in diabetics and suggest the possibility of using autologous macrophages/monocytes, treated with 14S,21R-diHDHA, or related compounds, to promote diabetes-impaired wound healing. (Am J Pathol

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Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction

Cited by 155 publications

References 32 publications

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

Shear Flow Attenuates Serum-induced STAT3 Activation in Endothelial Cells

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

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