Pathophysiology of the hepoxilins

Pace-Asciak, Cecil R.

doi:10.1016/j.bbalip.2014.09.007

Cited by 38 publications

(29 citation statements)

References 142 publications

(248 reference statements)

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“…Genomic LOX sequences occur in two domains (Bacteria, Eukarya) of terrestrial life (3). In mammals, LOXs have been implicated in the biosynthesis of lipid mediators (4,5), but they may also play a role in cell differentiation (6,7), apoptosis (8) and pathogenesis of inflammatory (9), hyperproliferative (10), and neurological (11) disorders. Targeted gene inactivation in mice provided useful information on the functionality of Alox12B (12R-lipoxygenase) (12) and Aloxe3 (epidermal lipoxygenase-3) (13), but Alox5 (5-lipoxygenase)- (14), Alox15- (15), and Alox12-deficient mice (16) do not show major defects unless challenged otherwise.…”

mentioning

confidence: 99%

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Adel

Karst

González‐Lafont

et al. 2016

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

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ALOX15 (12/15-lipoxygenase) orthologs have been implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids. Here we hypothesized that lower mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologs. In contrast, 15-lipoxygenating isoforms are found in higher primates (orangutans, men), and these results suggest an evolution of ALOX15 specificity. To test this hypothesis we first cloned and characterized ALOX15 orthologs of selected Catarrhini representing different stages of late primate evolution and found that higher primates (men, chimpanzees) express 15-lipoxygenating orthologs. In contrast, lower primates (baboons, rhesus monkeys) express 12-lipoxygenating enzymes. Gibbons, which are flanked in evolution by rhesus monkeys (12-lipoxygenating ALOX15) and orangutans (15-lipoxygenating ALOX15), express an ALOX15 ortholog with pronounced dual specificity. To explore the driving force for this evolutionary alterations, we quantified the lipoxin synthase activity of 12-lipoxygenating (rhesus monkey, mouse, rat, pig, humIle418Ala) and 15-lipoxygenating (man, chimpanzee, orangutan, rabbit, ratPhe353Ala) ALOX15 variants and found that, when normalized to their arachidonic acid oxygenase activities, the lipoxin synthase activities of 15-lipoxygenating ALOX15 variants were more than fivefold higher (P < 0.01). Comparative molecular dynamics simulations and quantum mechanics/molecular mechanics calculations indicated that, for the 15-lipoxygenating rabbit ALOX15, the energy barrier for C13-hydrogen abstraction (15-lipoxygenation) was 17 kJ/mol lower than for arachidonic acid 12-lipoxygenation. In contrast, for the 12-lipoxygenating Ile418Ala mutant, the energy barrier for 15-lipoxygenation was 10 kJ/mol higher than for 12-lipoxygenation. Taken together, our data suggest an evolution of ALOX15 specificity, which is aimed at optimizing the biosynthetic capacity for antiinflammatory and proresolving lipoxins.

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confidence: 99%

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Adel

Karst

González‐Lafont

et al. 2016

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

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“…Eicosanoids, which are formed from AA by the action of lipoxygenases, cyclooxygenases, and/or cytochrome P450, are widely implicated in lung inflammation by S. pneumoniae and other bacteria (27,31,67). We previously showed that pneumococcus-mediated induction of 12-LOX, an enzyme essential for the conversion of AA to the neutrophil chemoattractant HXA 3 , promotes basolateral-to-apical transepithelial recruitment of PMNs in vitro, as well as the corresponding apical-to-basolateral migration of bacteria (27).…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Phospholipase A₂α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

et al. 2017

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Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A 3 (HXA 3 ) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with S. pneumoniae. As phospholipase A 2 (PLA 2 ) promotes the release of AA, we investigated the role of PLA 2 in local and systemic disease during S. pneumoniae infection. The group IVA cytosolic isoform of PLA 2 (cPLA 2 ␣) was activated upon S. pneumoniae infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked S. pneumoniae-induced PMN transepithelial migration in vitro. Genetic ablation of the cPLA 2 isoform cPLA 2 ␣ dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae. The cPLA 2 ␣-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA 2 ␣ plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge.

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“…HXA 3 and LTB4 are both eicosanoid neutrophil chemoattractants generated by the lipoxygenase family of enzymes (19, 31, 32). HXA 3 plays a discrete role in mediating transepithelial migration, while LTB4 serves in a broad variety of functions as a leukocyte chemoattractant.…”

Section: Introductionmentioning

confidence: 99%

Distinct Cellular Sources of Hepoxilin A3 and Leukotriene B4 Are Used To Coordinate Bacterial-Induced Neutrophil Transepithelial Migration

Pazos

Pirzai

Yonker

et al. 2015

The Journal of Immunology

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Neutrophilic infiltration is a leading contributor to pathology in a number of pulmonary disease states including cystic fibrosis. Hepoxilin A3 (HXA3) is a chemotactic eicosanoid shown to mediate the transepithelial passage of neutrophils in response to infection in several model systems and at multiple mucosal surfaces. Another well known eicosanoid mediating general neutrophil chemotaxis is leukotriene B4 (LTB4). We sought to distinguish the roles of each eicosanoid in the context of infection of lung epithelial monolayers by Pseudomonas aeruginosa. Using human and mouse in vitro transwell model systems, we utilized a combination of biosynthetic inhibitors, receptor antagonists, as well as mutant sources of neutrophils to assess the contribution of each chemoattractant in driving neutrophil transepithelial migration. We found that following chemotaxis to epithelial-derived HXA3 signals, neutrophil-derived LTB4 is required to amplify the magnitude of neutrophil migration. LTB4 signaling is not required for migration to HXA3 signals, but LTB4 generation by migrated neutrophils plays a significant role in augmenting the initial HXA3-mediated migration. We conclude that HXA3 and LTB4 serve independent roles to collectively coordinate an effective neutrophilic transepithelial migratory response.

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Pathophysiology of the hepoxilins

Cited by 38 publications

References 142 publications

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Cytosolic Phospholipase A₂α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

Distinct Cellular Sources of Hepoxilin A3 and Leukotriene B4 Are Used To Coordinate Bacterial-Induced Neutrophil Transepithelial Migration

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Pathophysiology of the hepoxilins

Cited by 38 publications

References 142 publications

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection

Distinct Cellular Sources of Hepoxilin A3 and Leukotriene B4 Are Used To Coordinate Bacterial-Induced Neutrophil Transepithelial Migration

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Cytosolic Phospholipase A₂α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection