Production of oxidants in alveolar macrophages and blood leukocytes

Haugen, TS; Skjonsberg, OH; Kähler, Hanne; Lyberg, T

doi:10.1183/09031936.99.14511009

Cited by 28 publications

(23 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, in vitro experiments disclosed that OA-NO 2 blunted superoxide production in cultured PASMCs treated with PDGF and in LPS-stimulated macrophages, as assessed by ethidin quantification via HPLC analysis and cytochrome c reduction assay. Because macrophages are suggested to be the major cellular source of oxidants in the lung (32,33), the OA-NO 2 -dependent reduced pulmonary deposition of macrophages and the attenuation of superoxide release of macrophages in vitro strongly supports the anti-inflammatory and antioxidative effects of the nitrated fatty acids under hypoxic conditions. The diminished number of macrophages might be due to the impact of NO 2 -FA on decreasing the expression of leukocyte adhesion molecules such as VCAM-1 and ICAM-1 (11,16).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

Klinke

Möller²,

Pekarová

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO 2 ) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO 2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO 2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO 2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO 2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO 2 treatment. Moreover, OA-NO 2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO 2 . In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO 2 . Our results show that the oleic acid nitroalkene derivative OA-NO 2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO 2 represents a potential therapeutic agent for the treatment of PAH.Keywords: pulmonary arterial hypertension; nitro-fatty acids; inflammation; hypoxia Clinical RelevancePulmonary hypertension is a severe disease whose pathophysiology is incompletely understood and for which therapeutic options are limited. The present study enforces the hypothesis that inflammatory and oxidative mechanisms play an important role in the development of pulmonary hypertension. Electrophilic nitro-fatty acids decreased hypoxia-induced pulmonary hypertension not only by antiinflammatory and antioxidant mechanisms but also by reducing smooth muscle cell proliferation via attenuation of extracellular signal-regulated kinases 1 and 2 activation. These findings suggest that nitro-fatty acids may serve as a new multimodal therapeutic approach in this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

Klinke

Möller²,

Pekarová

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…Ligation of selected subsets of GPCRs is linked to the assembly and activation of NADPH oxidase and the release of free radicals associated with bacterial killing in the phagosomes of blood neutrophils (41), and to a much lesser extent in tissue macrophages (42). Stimulus-induced production of oxidants in tissue macrophages has been shown to be ∼110-fold less than that observed for blood phagosomes of blood neutrophils (43). In agreement with these findings, we were unable to observe an increase in oxidant (ROS) production in murine AMs challenged with bacteria following exposure to (R)-roscovitine (Fig.…”

Section: Direct Measurement Of (R)-roscovitine Induced Exocytotic Insmentioning

confidence: 99%

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Riazanski

Gabdoulkhakova

Boynton

et al. 2015

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

View full text Add to dashboard Cite

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H+ into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.

show abstract

“…H 2 O 2 can function as a progenitor of ROS like the highly reactive hydroxyl radical [196,197,216]. The fact that the induction of ex vivo mutagenesis by alveolar macrophages is significantly lower than by neutrophils could be explained by the fact that neutrophils have a higher potential to increase the ROSgeneration after activation than macrophages [217][218][219].…”

Section: Oxidative Stress-mediated Carcinogenesismentioning

confidence: 99%

Oxidant metabolism in chronic obstructive pulmonary disease

Boots

Haenen

Bast

2003

European Respiratory Journal

105

View full text Add to dashboard Cite

The development and progression of chronic obstructive pulmonary disease (COPD) have been associated with increased oxidative stress or reduced antioxidant resources. Several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products and degraded proteins, are indeed elevated in COPD patients. As a result, the antioxidant capacity decreases in COPD patients.The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect.COPD is linked to weight loss and in particular to loss in fat-free mass by skeletal muscle wasting. This systemic effect can be mediated by both oxidative stress and oxidative stress-mediated processes like apoptosis and inflammation. Furthermore, COPD is a predisposition for lung cancer through several mechanisms including oxidative stress and oxidative stress-mediated processes such as inflammation and disruption of genomic integrity.Current therapeutic interventions against the far-reaching consequences of the systemic oxidative stress in chronic obstructive pulmonary disease are not yet optimised. A diet designed to reduce chronic metabolic stress might form an effective therapeutic strategy in chronic obstructive pulmonary disease.

show abstract

Production of oxidants in alveolar macrophages and blood leukocytes

Cited by 28 publications

References 37 publications

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Oxidant metabolism in chronic obstructive pulmonary disease

Contact Info

Product

Resources

About