Leukotriene B4 levels in sputum from asthma patients

Higham, Andrew; Cadden, Paul; Southworth, Thomas; Rossall, Matthew; Kolsum, Umme; Lea, Simon; Knowles, Richard G.; Singh, Dave

doi:10.1183/23120541.00088-2015

Cited by 24 publications

(23 citation statements)

References 34 publications

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“…In contrast to the healthy airway (8, 13), LTB4 has been found at high levels in the asthmatic airway (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and this finding was confirmed in the current studies ( Figure 1). LTB4 contributes to asthma severity through its ability to recruit and activate PMNs, eosinophils, and CD8 1 cytotoxic lymphocytes (16)(17)(18)(19)(20)(21)(22).…”

Section: Discussionsupporting

confidence: 85%

“…LTB4 is produced from the sequential metabolism of arachidonic acid by 5-LO and LTA4 hydrolase (LTA4H). LTB4 is found at high levels in the asthmatic airway (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and engagement of its receptors, BLT1 and BLT2, contributes to the recruitment and activation of polymorphonuclear neutrophils (PMNs), eosinophils, and lymphocytes, in particular, CD8 1 cytotoxic T cells (16)(17)(18)(19)(20)(21)(22). What is less clear, however, is the source of LTB4 in asthmatic inflammation.…”

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confidence: 99%

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Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma

Pal

Feng

Steinke³

et al. 2019

Am J Respir Cell Mol Biol

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Asthma is associated with the overproduction of leukotrienes (LTs), including LTB4. Patients with severe asthma can be highly responsive to 5-lipoxygenase (5-LO) inhibition, which blocks production of both the cysteinyl LTs and LTB4. Production of LTB4 has traditionally been ascribed to neutrophils, mononuclear phagocytes, and epithelial cells, and acts as a chemoattractant for inflammatory cells associated with asthma. The source of LTB4 is unclear, especially in eosinophilic asthma. We speculated that the benefit of 5-LO inhibition could be mediated in part by inhibition of eosinophil-derived LTB4. LTB4 concentrations were assayed in BAL fluid from patients with severe asthma characterized by isolated neutrophilic, eosinophilic, and paucigranulocytic inflammation. Expression of LTA4 hydrolase (LTA4H) by airway eosinophils was determined by immunohistochemistry (IHC). Subsequently, peripheral blood eosinophils were activated and secreted LTB4 was quantified by enzyme immunoassay. Blood eosinophil LTA4H expression was determined by flow cytometry, qPCR, and IHC. LTB4 concentrations were elevated in BAL fluid from patients with severe asthma, including those with isolated eosinophilic inflammation, and these eosinophils displayed LTA4H via IHC. LTA4H expression by blood eosinophils was confirmed by flow cytometry, IHC, and qPCR. Robust LTB4 production by blood eosinophils was observed in response to some, but not all, stimuli. We demonstrated that eosinophils express LTA4H transcripts and protein, and can be stimulated to secrete LTB4. We speculate that in many patients with asthma, eosinophil-derived LTB4 is increased, and this may contribute to the efficacy of 5-LO inhibition.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma

Pal

Feng

Steinke³

et al. 2019

Am J Respir Cell Mol Biol

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“…Induced sputum was processed by a two-step method using phosphate-buffered saline (PBS) initially to obtain supernatant for protein analysis and then dithiothreitol (DTT) to obtain a cell pellet as previously described. 9 The supernatant was stored at -80°C for later analysis. Cytospin preparations (Cytospin 4, Shandon, Runcorn, UK) were stained with Rapi-Diff II (Atom Scientific, Hyde, UK).…”

Section: Methodsmentioning

confidence: 99%

The dose response of inhaled LPS challenge in healthy subjects

et al. 2018

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Lipopolysaccharide (LPS) inhalation causes neutrophilic airway inflammation. We used LPS produced to Good Manufacturing Practice (GMP) standards to characterise the dose response. A total of 15 healthy non-smoking subjects inhaled 5-, 15-and 50-µg LPS. Whole blood cell counts and serum C-reactive protein (CRP) were measured at baseline and up to 24 h post challenge. Sputum was induced at baseline and 6 h post challenge for cell counts and quantification of myeloperoxidase (MPO), interleukin (IL)-1β, IL-6, IL-8 and tumour necrosis factor α (TNF-α) in supernatants. LPS inhalation was well tolerated. Blood neutrophil counts increased at 6 h post LPS with all doses. Serum CRP significantly increased with 15-and 50-µg LPS. All LPS doses significantly increased sputum neutrophil percentage (P < 0.001). IL-1β, IL-6 and TNF-α were significantly increased in sputum supernatant following challenge with 50-µg LPS, there was no change in MPO or IL-8. The 50-µg LPS was well tolerated and produced a robust inflammatory response. This study supports the use of 50-µg GMP-grade LPS as a suitable challenge agent in clinical trials.

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“…In fact, increased neutrophil counts have been detected in the sputum, peripheral blood and bronchoalveolar lavage fluid of patients who have severe or steroid-resistant asthma [52,53,54]. Several factors have been found to be associated with neutrophil accumulation: (i) dysbiosis, in which a predominance of specific bacterial species accounts for excessive recruitment of neutrophils [55]; (ii) increased levels of chemokines and pro-inflammatory cytokines, including CXCL1, CXCL5, IL-1β, IFNγ, and IL-6, which promote the recruitment of neutrophils [56]; (iii) high levels of LTB4, a potent chemoattractant and pro-survival factor for neutrophils [57,58]; (iv) inadequate removal of dead neutrophils or inhibition of their apoptosis (although this hypothesis has recently come under question) [54,59]. In this context, GC treatment can exacerbate these events and promote neutrophilia.…”

Section: Neutrophils Disease and Gc Treatmentmentioning

confidence: 99%

How Glucocorticoids Affect the Neutrophil Life

Ronchetti

Migliorati

Gentili

et al. 2018

IJMS

147

135

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Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions.

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Leukotriene B4 levels in sputum from asthma patients

Cited by 24 publications

References 34 publications

Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma

Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma

The dose response of inhaled LPS challenge in healthy subjects

How Glucocorticoids Affect the Neutrophil Life

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