89 results found
Giblin SP, Ranawana S, Hassibi S, et al., 2023, CXCL17 binds efficaciously to glycosaminoglycans with the potential to modulate chemokine signaling, Frontiers in Immunology, Vol: 14, ISSN: 1664-3224
Introduction: CXCL17 is a mucosally secreted protein, and the most recently identified human chemokine, an assignment based on protein fold prediction and chemotactic activity for leukocytes. However, these credentials have been the subject of much recent discussion and no experimental evidence has been presented regarding the definitive structure of CXCL17. In this study, we evaluated the structural and chemoattractant credentials of CXCL17 to better characterize this molecule, and gain deeper insights into its functional role as a glycosaminoglycan (GAG) binding protein.Methods: In the absence of structural information, in silico modeling techniques assessed the likelihood of CXCL17 adopting a chemokine fold. Recombinant CXCL17 was synthesized in mammalian and prokaryotic systems. Modified Boyden chamber and real-time chemotaxis assays assessed the ability of CXCL17 to promote chemotaxis of murine splenocytes, human neutrophils, and CXCR1 transfectants. The efficacy of CXCL17 binding to GAGs was quantified with solid-phase assays and bio-layer interferometry techniquesResults: All modeling efforts failed to support classification of CXCL17 as a chemokine based on its predicted conformation. Recombinant CXCL17 was observed to dimerize as a function of concentration, a characteristic of several chemokines. Contrary to a previous report, CXCL17 was not chemotactic for murine splenocytes, although it was a low-potency chemoattractant for human neutrophils at micromolar concentrations, several orders of magnitude higher than those required for CXCL8. As anticipated owing to its highly basic nature, CXCL17 bound to GAGs robustly, with key C-terminal motifs implicated in this process. While inactive via CXCR1, CXCL17 was found to inhibit CXCR1-mediated chemotaxis of transfectants to CXCL8 in a dose-dependent manner.Discussion: In summary, despite finding little evidence for chemokine-like structure and function, CXCL17 readily bound GAGs, and could modulate chemotactic r
Almond M, Jackson M, Jha A, et al., 2023, Obesity dysregulates the pulmonary antiviral immune response, Nature Communications, Vol: 14, ISSN: 2041-1723
Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.
Madison MC, Margaroli C, Genschmer KR, et al., 2023, Protease-armed, pathogenic extracellular vesicles link smoking and COPD, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
RATIONALE: Mounting evidence demonstrates a role for extracellular vesicles (EVs) in driving lung disorders, such as COPD. While cigarette smoke (CS) is the primary risk factor for COPD, a link between CS and the EVs that could lead to COPD is unknown. OBJECTIVE: To ascertain whether exposure to CS elicits a proteolytic EV signature capable of driving disease pathogenesis. METHODS: Protease expression and enzymatic activity was measured in EVs harvested from the BAL fluid of smoke-exposed mice and otherwise healthy human smokers. Pathogenicity of EVs was examined using pathological tissue scoring following EV transfer into naïve recipient mice. MEASUREMENTS & MAIN RESULTS: Our analyses reveal a unique EV profile defined by neutrophil and macrophage-derived EVs. These EVs are characterized by abundant surface expression of neutrophil elastase (NE) and matrix metalloproteinase (MMP-12), respectively. CS-induced mouse or human-derived airway EVs had a robust capacity to elicit rapid lung damage in naïve recipient mice, with an additive effect of NE and MMP-12-expressing EVs. CONCLUSIONS: These studies demonstrate the capacity of CS to drive the generation of unique EV populations containing NE and MMP-12. The coordinated action of these EVs is completely sufficient to drive emphysematous disease, and their presence could operate as a prognostic indicator for COPD development. Furthermore, given the robust capacity of these EVs to elicit emphysema in naïve mice, they provide a novel model to facilitate pre-clinical COPD research. Indeed, the development of this model has led to the discovery of a previously unrecognized CS-induced protective mechanism against EV-mediated damage.
Beech A, Portacci A, Herrero-Cortina B, et al., 2023, ERS International Congress 2022: highlights from the Airway Diseases Assembly, ERJ OPEN RESEARCH, Vol: 9
Mincham KT, Snelgrove RJ, 2023, OMIP-086: Full spectrum flow cytometry for high-dimensional immunophenotyping of mouse innate lymphoid cells, Cytometry Part A, Vol: 103, Pages: 110-116, ISSN: 1552-4922
This 25-parameter, 22-color full spectrum flow cytometry panel was designed and optimized for the comprehensive enumeration and functional characterization of innate lymphoid cell (ILC) subsets in mouse tissues. The panel presented here allows the discrimination of ILC progenitors (ILCP), ILC1, ILC2, NCR+ ILC3, NCR− ILC3, CCR6+ lymphoid tissue-inducer (LTi)-like ILC3 and mature natural killer (NK) cell populations. Further characterization of ILC and NK cell functional profiles in response to stimulation is provided by the inclusion of subset-specific cytokine markers, and proliferation markers. Development and optimization of this panel was performed on freshly isolated cells from adult BALB/c lungs and small intestine lamina propria, and ex vivo stimulation with phorbol 12-myrisate 13-acetate, ionomycin, and pro-ILC activating cytokines.
Pyle C, Patel D, Peiro T, et al., 2022, MMP-12 supports pulmonary B cell follicle formation and local antibody responses during asthma, American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 1424-1428, ISSN: 1073-449X
Bruno N, Singanayagam A, Farne HA, et al., 2022, G-CSF drives pathophysiology of RV-induced allergic asthma exacerbations by potentiating neutrophilic inflammation and ILC2 function, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Vijayakumar B, Boustani K, Ogger P, et al., 2022, Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVD-19 respiratory disease, Immunity, Vol: 55, Pages: 542-556.e5, ISSN: 1074-7613
Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airway and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. 1 year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.
Byrne AJ, Saglani S, Snelgrove RJ, 2022, An Alarmin Role for P2Y<sub>13</sub> Receptor during Viral-driven Asthma Exacerbations, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 263-265, ISSN: 1073-449X
Mincham KT, Bruno N, Singanayagam A, et al., 2021, Our evolving view of neutrophils in defining the pathology of chronic lung disease, IMMUNOLOGY, Vol: 164, Pages: 701-721, ISSN: 0019-2805
Kobold N, Dekkak B, Flajolet P, et al., 2020, Characterisation of type two immune responses in a murine model of allergic airway disease, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Harker JA, Snelgrove RJ, 2020, A Not-So-Good Way to Die? Respiratory Syncytial Virus-induced Necroptotic Cell Death Promotes Inflammation and Type 2-mediated Pathology, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 201, Pages: 1321-1323, ISSN: 1073-449X
Turnbull A, Pyle C, Patel D, et al., 2020, Abnormal pro-gly-pro pathway and airway neutrophilia in pediatric cystic fibrosis, Journal of Cystic Fibrosis, Vol: 19, Pages: 40-48, ISSN: 1569-1993
BackgroundProline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms.MethodsBroncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed.ResultsWhilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase.ConclusionsA striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia.
Patel DF, Peiro T, Bruno N, et al., 2019, Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation, Science Immunology, Vol: 4, Pages: 1-18, ISSN: 2470-9468
Neutrophil mobilization, recruitmentand clearancemust be tightly regulated asover-exuberant neutrophilic inflammation isimplicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophilstherapeutically have failed to consider theirpleiotropic functions and theimplications of disrupting fundamental regulatory pathways that govern their turnover duringhomeostasisand inflammation.Using thehouse dust mite(HDM)model of allergic airways disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated TH2 inflammation, epithelial remodelling and airway resistance. Mechanistically, this was attributable to astriking increase insystemic G-CSF concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increasedG-CSF augmented allergic sensitization in HDM exposed animals bydirectly acting on airway ILC2s toelicitcytokine production.Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool.By modelling the effects of neutrophil depletion, our studies have therefore uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly,they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.
Singanayagam A, Snelgrove RJ, 2019, Less burn, more fat: electronic cigarettes and pulmonary lipid homeostasis, JOURNAL OF CLINICAL INVESTIGATION, Vol: 129, Pages: 4077-4079, ISSN: 0021-9738
Salek-Ardakani S, Bell T, Jagger CP, et al., 2019, CD200R1 regulates eosinophilia during pulmonary fungal infection in mice, EUROPEAN JOURNAL OF IMMUNOLOGY, ISSN: 0014-2980
Snelgrove RJ, Patel DF, 2019, Zooming into the Matrix: Using Nonlinear Optical Microscopy to Visualize Collagen Remodeling in Asthmatic Airways, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 403-413, ISSN: 1073-449X
Bell TJ, Brand OJ, Morgan DJ, et al., 2019, Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis, MATRIX BIOLOGY, Vol: 80, Pages: 14-28, ISSN: 0945-053X
Patel DF, Gaggar A, Blalock JE, et al., 2019, Response to Comment on "An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness", SCIENCE TRANSLATIONAL MEDICINE, Vol: 11, ISSN: 1946-6234
Dean CH, Snelgrove RJ, 2018, New rules for club development: new insights into human small airway epithelial club cell ontogeny and function, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1355-1366, ISSN: 1073-449X
Snelgrove RJ, Patel DF, Patel T, et al., 2018, The enigmatic role of the neutrophil in asthma: Friend, foe or indifferent?, Clinical and Experimental Allergy, Vol: 48, Pages: 1275-1285, ISSN: 0954-7894
Whilst severe asthma has classically been categorized as a predominantly Th2-driven pathology, there has in recent years been a paradigm shift with the realization that it is a heterogeneous disease that may manifest with quite disparate underlying inflammatory and remodelling profiles. A subset of asthmatics, particularly those with a severe, corticosteroid refractory disease, present with a prominent neutrophilic component. Given the potential of neutrophils to impart extensive tissue damage and promote inflammation, it has been anticipated that these cells are closely implicated in the underlying pathophysiology of severe asthma. However, uncertainty persists as to why the neutrophil is present in the asthmatic lung and what precisely it is doing there, with evidence supporting its role as a protagonist of pathology being primarily circumstantial. Furthermore, our view of the neutrophil as a primitive, indiscriminate killer has evolved with the realization that neutrophils can exhibit a marked anti-inflammatory, pro-resolving and wound healing capacity. We suggest that the neutrophil likely exhibits pleiotropic and potentially conflicting roles in defining asthma pathophysiology-some almost certainly detrimental and some potentially beneficial-with context, timing and location all critical confounders. Accordingly, indiscriminate blockade of neutrophils with a broad sword approach is unlikely to be the answer, but rather we should first seek to understand their complex and multifaceted roles in the disease state and then target them with the same subtleties and specificity that they themselves exhibit.
Patel D, Peiro T, Shoemark A, et al., 2018, An extracellular matrix fragment drives epithelial remodeling and airway hyper-responsiveness, Science Translational Medicine, Vol: 10, Pages: 1-13, ISSN: 1946-6234
It is anticipated that bioactive fragments of the extracellular matrix (matrikines) can influence the development and progression of chronic diseases. The enzyme leukotriene A4 hydrolase (LTA4H) mediates opposing proinflammatory and anti-inflammatory activities, through the generation of leukotriene B4 (LTB4) and degradation of proneutrophilic matrikine Pro-Gly-Pro (PGP), respectively. We show that abrogation of LTB4 signaling ameliorated inflammation and airway hyperresponsiveness (AHR) in a murine asthma model, yet global loss of LTA4H exacerbated AHR, despite the absence of LTB4. This exacerbated AHR was attributable to a neutrophil-independent capacity of PGP to promote pathological airway epithelial remodeling. Thus, we demonstrate a disconnect between airway inflammation and AHR and the ability of a matrikine to promote an epithelial remodeling phenotype that negatively affects lung function. Subsequently, we show that substantial quantities of PGP are detectable in the sputum of moderate-severe asthmatics in two distinct cohorts of patients. These studies have implications for our understanding of remodeling phenotypes in asthma and may rationalize the failure of LTA4H inhibitors in the clinic.
Snelgrove RJ, Lloyd CM, 2018, Tasting type 2 inflammation in the airways, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 403-404, ISSN: 0091-6749
Lloyd CM, Snelgrove RJ, 2018, Type 2 immunity: expanding our view., Science Immunology, Vol: 3, ISSN: 2470-9468
The classical vision of type 2 immune reactions is that they are characterized by a distinct cellular and cytokine repertoire that is critical for host resistance against helminthic worm infections but, when dysregulated, may cause atopic reactions that result in conditions such as asthma, rhinitis, dermatitis, and anaphylaxis. In this traditional view, the type 2 response is categorized as an adaptive immune response with differentiated T helper cells taking center stage, driving eosinophil recruitment and immunoglobulin production via the secretion of a distinct repertoire of cytokines that include interleukin-4 (IL-4), IL-5, and IL-13. The recent discovery of a group of innate cells that has the capacity to secrete copious amounts of type 2 cytokines, potentially in the absence of adaptive immunity, has reignited interest in type 2 biology. The discovery that these innate lymphoid cells and type 2 cytokines are involved in diverse biological processes-including wound healing, control of metabolic homeostasis, and temperature-has considerably changed our view of type 2 responses and the cytokines, chemokines, and receptors that regulate these responses.
Patel DF, Snelgrove RJ, 2018, The multifaceted roles of the matrikine Pro-Gly-Pro in pulmonary health and disease, European Respiratory Review, Vol: 27, ISSN: 0905-9180
Matrikines are bioactive fragments of the extracellular matrix (ECM) that are fundamental in regulating a diverse array of physiological processes. The tripeptide Proline-Glycine-Proline (PGP) is a collagen-derived matrikine that has classically been described as a neutrophil chemoattractant. In this article, we describe our current understanding of the pathways that generate, degrade and modify PGP to dictate its bioavailability and stability. Additionally, we discuss our expanding appreciation of the capacity of PGP to regulate diverse cell types and biological processes, independent of its activity on neutrophils, including a putative role in wound repair. We argue that PGP functions as a primitive and conserved damage-associated molecular pattern, which is generated during infection or injury and subsequently acts to shape ensuing inflammatory and repair processes. As a fragment of the ECM that accumulates at the epicentre of the action, PGP is perfectly positioned to focus neutrophils to the exact site required and direct a localised repair response. However, it is essential that PGP is efficiently degraded, as if this matrikine is allowed to persist then pathology can ensue. Accordingly, we discuss how this pathway is subverted in chronic lung diseases giving rise to persistent inflammation and pathological tissue remodelling.
O'Reilly PJ, Ding Q, Akthar S, et al., 2017, Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis, JCI INSIGHT, Vol: 2, ISSN: 2379-3708
The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis. We demonstrate that AcPGP is degraded through a previously unidentified action of the enzyme angiotensin-converting enzyme (ACE). Pulmonary ACE is elevated during episodes of acute inflammation, as a consequence of enhanced vascular permeability, to ensure the efficient degradation of AcPGP. Conversely, we suggest that this pathway is aberrant in chronic obstructive pulmonary disease (COPD) enabling the accumulation of AcPGP. Consequently, we identify a potentially novel protective role for AcPGP in limiting pulmonary fibrosis and suggest the pathogenic function attributed to ACE in idiopathic pulmonary fibrosis (IPF) to be a consequence of overzealous AcPGP degradation. Thus, AcPGP seemingly has very divergent roles: it is pathogenic in its capacity to drive neutrophilic inflammation and matrix degradation in the context of COPD, but it is protective in its capacity to limit fibrosis in IPF.
Peiró T, Patel DF, Akthar S, et al., 2017, Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection, Thorax, Vol: 73, Pages: 546-556, ISSN: 1468-3296
Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.
Snelgrove RJ, Lloyd CM, 2017, An NLRP3, IL-1 beta, Neutrophil Axis in the Respiratory Tract Leaves You Breathless, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 253-254, ISSN: 1073-449X
Baker K, Raemdonck K, Snelgrove RJ, et al., 2017, Characterisation of a murine model of the late asthmatic response, Respiratory Research, Vol: 18, ISSN: 1465-9921
Background: The incidence of asthma is increasing at an alarming rate. While the current available therapies areeffective, there are associated side effects and they fail to adequately control symptoms in all patient subsets. In thesearch to understand disease pathogenesis and find effective therapies hypotheses are often tested in animalmodels before progressing into clinical studies. However, current dogma is that animal model data is often notpredictive of clinical outcome. One possible reason for this is the end points measured such as antigen-challengeinduced late asthmatic response (LAR) is often used in early clinical development, but seldom in animal modelsystems. As the mouse is typically selected as preferred species for pre-clinical models, we wanted to characteriseand probe the validity of a murine model exhibiting an allergen induced LAR.Methods: C57BL/6 mice were sensitised with antigen and subsequently topically challenged with the sameantigen. The role of AlumTM adjuvant, glucocorticoid, long acting muscarinic receptor antagonist (LAMA), TRPA1,CD4+ and CD8+ T cells, B cells, Mast cells and IgE were determined in the LAR using genetically modified mice anda range of pharmacological tools.Results: Our data showed that unlike other features of asthma (e.g. cellular inflammation, elevated IgE levels andairway hyper-reactivity (AHR) the LAR required AlumTMadjuvant. Furthermore, the LAR appeared to be sensitive toglucocorticoid and required CD4+ T cells. Unlike in other species studied, the LAR was not sensitive to LAMAtreatment nor required the TRPA1 ion channel, suggesting that airway sensory nerves are not involved in the LARin this species. Furthermore, the data suggested that CD8+ T cells and the mast cell—B-cell - IgE axis appear to beprotective in this murine model.Conclusion: Together we can conclude that this model does feature steroid sensitive, CD4+ T cell dependent,allergen induced LAR. However, collectively our data questions the validit
Low CM, Akthar S, Patel D, et al., 2017, The development of novel LTA4H modulators to selectively target LTB4 generation, Scientific Reports, Vol: 7, ISSN: 2045-2322
The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.
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