The cytokines of pulmonary fibrosis: Much learned, much more to learn

Luzina, Irina G.; Todd, Nevins W.; Sundararajan, Sripriya; Atamas, Sergei P.

doi:10.1016/j.cyto.2014.11.008

Cited by 92 publications

(94 citation statements)

References 240 publications

(289 reference statements)

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“…The elevations of IL-6, MCP-1, and TGF-b, which are well known for their profibrotic activities (Luzina et al, 2015), were significantly attenuated by SPL-334, whereas the levels of protective cytokines IFN-g and TNF-a (Redente et al, 2014;Luzina et al, 2015) were significantly increased or tended to be elevated, respectively, by SPL-334 (Fig. 3).…”

Section: Spl-334 Attenuates Inflammation and Fibrosis In The Lungsmentioning

confidence: 92%

“…In light of the central involvement of cytokines in the mechanisms of pulmonary inflammation and fibrosis (Luzina et al, 2015), levels of IL-1b, IL-4, IL-6, KC, MCP-1, MIP-1a, IFN-g, and TNF-a were measured in mouse lung homogenates utilizing multiplex assays at days 14 and 21 in the therapeutic treatment regimen, whereas the levels of total TGF-b were measured by enzyme-linked immunosorbent assay. The levels of the majority of these cytokines were significantly elevated in the lung homogenates of BLM-challenged animals compared with PBS-challenged controls, and SPL-334 further significantly affected pulmonary levels of cytokines (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Luzina

Lockatell

Todd

et al. 2015

J Pharmacol Exp Ther

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Interstitial lung disease (ILD) characterized by pulmonary fibrosis and inflammation poses a substantial biomedical challenge due to often negative disease outcomes combined with the need to develop better, more effective therapies. We assessed the in vivo effect of administration of a pharmacological inhibitor of Snitrosoglutathione reductase, SPL-334, in a mouse model of ILD induced by intratracheal instillation of bleomycin (BLM). Daily i.p. administration of SPL-334 alone at 0.3, 1.0, or 3.0 mg/kg had no effect on animal body weight, appearance, behavior, total and differential bronchoalveolar lavage (BAL) cell counts, or collagen accumulation in the lungs, showing no toxicity of our investigational compound. Similar administration of SPL-334 for 7 days before and for an additional 14 days after BLM instillation resulted in a preventive protective effect on the BLM challenge-induced decline in total body weight and changes in total and differential BAL cellularity. In the therapeutic treatment regimen, SPL-334 was administered at days 7-21 after BLM challenge. Such treatment attenuated the BLM challenge-induced decline in total body weight, changes in total and differential BAL cellularity, and magnitudes of histologic changes and collagen accumulation in the lungs. These changes were accompanied by an attenuation of BLMinduced elevations in pulmonary levels of profibrotic cytokines interleukin-6, monocyte chemoattractant protein-1, and transforming growth factor-b (TGF-b). Experiments in cell cultures of primary normal human lung fibroblast have demonstrated attenuation of TGF-b-induced upregulation in collagen by SPL-334. It was concluded that SPL-334 is a potential therapeutic agent for ILD.

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Section: Spl-334 Attenuates Inflammation and Fibrosis In The Lungsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Luzina

Lockatell

Todd

et al. 2015

J Pharmacol Exp Ther

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“…Because ILC2s have recently been associated with fibrotic diseases where type 2 cytokines are considered the most potent profibrotic factors through direct activation of fibroblasts [42,43], it is conceivable that ILC2s also contribute to airway remodeling in asthma. In agreement with this, chronic exposure of mice to a cocktail of Alternaria, Aspergillus, and HDM was shown to induce robust airway inflammation, hyperresponsiveness, and remodeling by a mechanism dependent on adaptive immunity [44].…”

Section: Discussionmentioning

confidence: 99%

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Bruijn

Tindemans

et al. 2016

Eur J Immunol

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Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL-5 and IL-13. Here, we used a house dust mite (HDM)-driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T-cell activation precedes ILC2 induction. During HDM-driven allergic airway inflammation the accumulation of ILC2s in BALF is IL-33 independent, although infiltrating ILC2s produce less cytokines in Il33 −/− mice. Transfer of in vitro polarized OVA-specific OT-II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T-cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM-mediated allergic airway inflammation in mice critically depends on activation of T cells.Keywords: Allergy · Asthma · Group 2 innate lymphoid cells (ILC2s) · House dust mite · Th2 cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAsthma is a heterogeneous disease involving chronic inflammation of the airways and is characterized by episodes of coughing, wheezing, and shortness of breath. Multiple genetic predispositions and environmental factors contribute to asthma development and it is estimated that ß300 million people are affected worldwide. The asthma syndrome is divided into distinct disease entities with specific mechanisms, which have been called asthma endotypes [1,2]. The most prevalent endotype is allergic asthma, showing a strong association between exacerbations and repeated Correspondence: Dr. Rudi W. Hendriks e-mail: r.hendriks@erasmusmc.nl exposure to allergens such as pollen, fungi, or house dust mite (HDM). Allergic asthma is thought to be a classic Th2-mediated disease in which the signature effector cytokines IL-4, IL-5, and IL-13 are key orchestrators of persistent inflammation, airway hyperresponsiveness and remodeling, smooth muscle cell hyperplasia, mucous cell metaplasia, and increased angiogenesis (reviewed in [2,3]).Although production of IL-5 and IL-13 by a non-T/non-B lymphocyte population in response to IL-25 was first reported by Fort et al. [4], only recently these cells were accurately characterized and defined as a novel cell population that is negative for classic hematopoietic lineage markers and expresses Sca-1, CD117 (c-kit), CD25 (IL-2Rα), CD127 (IL-7Rα), and T1/ST2 (IL-33R) [5][6][7]. These innate cells are currently referred to as group 2 innate lymphoid cells (ILC2s) and were found to produce IL-13, which is [24]. Ho...

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“…IL-6 is a pro-inflammatory cytokine; however, the important anti-inflammatory and regenerative nature of IL-6 has also been described 18 . Furthermore, the IL-6-mediated profibrotic properties through the direct activation of fibroblasts and numerous indirect mechanisms have been reviewed 16,19 . IL-7 is also a cytokine with pleiotropic functions; however, IL-7 mostly functions as an immunoregulatory cytokine.…”

Section: Introductionmentioning

confidence: 99%

“…IL-4 is a key cytokine in the development of allergic inflammation and an important local factor participating in cell signalling due to allergen exposure 15 . IL-4 increases fibroblast proliferation and the secretion of extracellular matrix components leading to fibrosis 16 . IL-4 also highly promotes the pathogenesis of both allergy and asthma 17 .…”

Section: Introductionmentioning

confidence: 99%

Inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue as an essential part of the local immune system

Vitenberga¹,

Pilmane²

2017

BIOMED PAP

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Background. The innate and adaptive immune systems in lungs are maintained not only by immune cells but also by non-immune tissue structures, locally providing wide intercellular communication networks and regulating the local tissue immune response. Aims. The aim of this study was to determine the appearance and distribution of inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue samples. Material and Methods. We evaluated lung tissue specimens obtained from 49 patients aged 9-95 years in relatively healthy study subjects. Tissue samples were examined by hematoxylin and eosin staining. Interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), and interleukin-10 (IL-10) were detected by an immunohistochemistry (IMH) method. The number of positive structures was counted semiquantitatively by microscopy. Non-parametric tests were used to analyse the data. Results. IL-1-positive cells were mostly found in the bronchial cartilage and alveolar epithelium. Immunoreactive lung macrophages were also found. The numbers of IL-4, IL-6, IL-7, and IL-10 containing cells were also found in the bronchial epithelium (in addition to those previously listed). The number of positive structures varied from occasional to moderate, but was graded higher in cartilage. Overall, fewer IL-1-positive cells and more IL-10-positive cells were found. Almost no positive structures for all examined cytokines were found in connective tissue and bronchial glands. Conclusions. Relatively healthy lung tissue exhibits anti-inflammatory response patterns. The cytokine distribution and appearance suggest persistent stimulation of cytokine expression in lung tissue and indicate the presence of local regulatory and modulating patterns. The pronounced cytokine distribution in bronchial cartilage suggests the involvement of a compensatory local immune response in the supporting tissue.

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The cytokines of pulmonary fibrosis: Much learned, much more to learn

Cited by 92 publications

References 240 publications

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

Pharmacological In Vivo Inhibition of S-Nitrosoglutathione Reductase Attenuates Bleomycin-Induced Inflammation and Fibrosis

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue as an essential part of the local immune system

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