Pulmonary Antifibrotic Mechanisms Aspirin-Triggered Lipoxin A<sub>4</sub> Synthetic Analog

Guilherme, Rafael F.; Xisto, Débora G.; Kunkel, Steven L.; Freire-de-Lima, Célio Geraldo; Rocco, Patricia R. M.; Neves, Josiane S.; Fierro, Iolanda M.; Canetti, Cláudio; Benjamim, Cláudia F.

doi:10.1165/rcmb.2012-0462oc

Cited by 34 publications

(32 citation statements)

References 48 publications

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“…This is supported by a study showing the role of lipoxins in cell therapy‐mediated lung repair, where human bone‐marrow‐derived MSCs induced production of LXA4 by alveolar epithelial cells in a mouse model of LPS‐induced acute lung injury []. Guilherme and colleagues showed that LXA4 analogs were potent anti‐inflammatory and antifibrotic compounds in a bleomycin‐induced model of lung injury []. We thus focused our attention on lipoxin A 4 a key regulator of macrophage infiltration and function in hAEC‐mediated repair of lung fibrosis.…”

Section: Discussionmentioning

confidence: 86%

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Tan

Muljadi

et al. 2016

Stem Cells Translational Medicine

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Human amnion epithelial cells (hAECs) have been shown to possess potent immunomodulatory properties across a number of disease models. Recently, we reported that hAECs influence macrophage polarization and activity, and that this step was dependent on regulatory T cells. In this study, we aimed to assess the effects of hAEC‐derived proresolution lipoxin‐A4 (LXA4) on T‐cell, macrophage, and neutrophil phenotype and function during the acute phase of bleomycin‐induced lung injury. Using C57Bl6 mice, we administered 4 million hAECs intraperitoneally 24 hours after bleomycin challenge. Outcomes were measured at days 3, 5, and 7. hAEC administration resulted in significant changes to T‐cell, macrophage, dendritic cell, and monocyte/macrophage infiltration and phenotypes. Endogenous levels of lipoxygenases, LXA4, and the lipoxin receptor FPR2 were elevated in hAEC‐treated animals. Furthermore, we showed that the effects of hAECs on macrophage phagocytic activity and T‐cell suppression are LXA4 dependent, whereas the inhibition of neutrophil‐derived myleoperoxidase by hAECs is independent of LXA4. This study provides the first evidence that lipid‐based mediators contribute to the immunomodulatory effects of hAECs and further supports the growing body of evidence that LXA4 is proresolutionary in lung injury. This discovery of LXA4‐dependent communication between hAECs, macrophages, T cells, and neutrophils is important to the understanding of hAEC biodynamics and would be expected to inform future clinical applications. Stem Cells Translational Medicine 2017;6:1085–1095

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Section: Discussionmentioning

confidence: 86%

Amnion Epithelial Cells Promote Lung Repair via Lipoxin A4

Tan

Muljadi

et al. 2016

Stem Cells Translational Medicine

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“…Bleomycin is an important chemotherapeutic agent but carries a known risk of pulmonary fibrosis. Treatment with LXA 4 or 15-epi-LXA 4 results in an attenuation of pulmonary fibrosis in animals exposed to bleomycin through reduction of the pro-fibrotic cytokine TGFβ 132 , as well as an increase in the prevalence of M2 macrophages 133 , both resulting in decrease fibrotic matrix and improved pulmonary function. In humans, scleroderma lung disease is characterized by idiopathic progressive lung inflammation and fibrosis and, of interest, patients with scleroderma lung disease underproduce pro-resolving mediators, in comparison to their pro-inflammatory counterparts 134 .…”

Section: Spms In Chronic Inflammatory Diseasesmentioning

confidence: 99%

Specialized pro-resolving mediators: endogenous regulators of infection and inflammation

2015

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Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids and have important roles in orchestrating the resolution of tissue inflammation -that is, catabasis. Host responses to tissue infection elicit acute inflammation in an attempt to control invading pathogens. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Here, we focus primarily on SPMs and their roles in lung infection and inflammation to illustrate the potent actions these mediators play in restoring tissue homeostasis after an infection.Acute inflammation is a vital response to infection that is initiated within seconds of pathogen detection 1 . Granulocytes are rapidly recruited to sites of infection 2 , where they become activated and augment the resident capacity of infected tissue to kill and ultimately clear the pathogen 3 . These early events in the host response to infection are essential for survival and are coordinated by several families of pro-inflammatory mediators, including lipid mediators (such as prostaglandins and leukotrienes), cytokines and chemokines. These pro-inflammatory mediators have overlapping and distinct functions and ultimately induce an increase in vascular permeability and orchestrate leukocyte recruitment. This leads to the cardinal signs of tissue inflammation -namely calor, rubor, tumor, dolor and potentially functio laesa (FIG. 1).Recently, a new array of molecules that function in the resolution of inflammation were elucidated and named specialized pro-resolving mediators (SPMs) 4,5 . Many of these SPMs are produced during the acute inflammatory response 6 , and their structure, biosynthesis and organic synthesis have been recently reviewed (see REF. 5). Typically, acute inflammatory responses to pathogens are self-limiting, and there is a growing appreciation that SPMs have pivotal anti-inflammatory and anti-infective roles in tissue catabasis 4 . For effective Correspondence to B.D.L. blevy@partners.org. Competing interests statementThe authors declare competing interests: see Web version for details. DATABASES ClinicalTrials.gov: http://www.clinicaltrials.gov ALL LINKS ARE ACTIVE IN THE ONLINE PDF HHS Public AccessAuthor manuscript Nat Rev Immunol. Author manuscript; available in PMC 2017 January 18. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript resolution of inflammation to occur in tissues, cessation of granulocyte recruitment is required in conjunction with the recruitment and differentiation of macrophages, which help clear inflammatory cells and tissue debris to restore tissue homeostasis 7 . Granulocytes in the tissue undergo apoptosis during the resolution of inflammation to prevent bystander tissue injury occurring from the release of potentially toxic cellular conten...

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“…15,16 Furthermore, there are publications showing strong beneficial effects of lipoxin A4 or its more stable analogs in preventing myofibroblast formation 17 and bleomycin-induced fibrosis 18 and in improving lung function of bleomycin-treated mice. 19 Interestingly, CD45 1 fibrocytes, which show mesenchymal properties such as collagen type 1 or fibroblast specific protein 1 (FSP) expression, 20 have been suggested to express E-type prostanoid 2 (EP2), EP4, and I-type prostanoid receptors. 21 Abbreviations It has been demonstrated that patients with IPF show significantly lower levels of PGs, particularly PGE 2 , in the bronchoalveolar lavage (BAL).…”

mentioning

confidence: 99%