Innate Immune Activation by Inhaled Lipopolysaccharide, Independent of Oxidative Stress, Exacerbates Silica-Induced Pulmonary Fibrosis in Mice

Brass, David M.; Spencer, Jennifer; Li, Zhuowei; Potts-Kant, Erin N.; Reilly, Sarah; Dunkel, Mary K.; Latoche, Joseph D.; Auten, Richard L.; Hollingsworth, John W.; Fattman, Cheryl L.

doi:10.1371/journal.pone.0040789

Cited by 14 publications

(7 citation statements)

References 43 publications

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“…In support of the present hypothesis, 5-day inhalation exposure (2.5 h/day) to E. coli LPS aerosol (0.5 lg/m 3 ) exacerbated silicosis in mice (Brass et al, 2012), although it has been demonstrated that 5-day inhalation exposure (4 h/ day) to the same LPS aerosol alone (0.21 lg/m 3 ) induced BALF IL-1b in normal mice (Brass et al, 2003). In addition, a significant amount of LPS (120 ± 64 ng of E. coli LPS equivalent) was found in cigarette smoke (Hasday et al, 1999), which is well acknowledged as a risk factor for silicosis (WHO, 2000) and other idiopathic pulmonary fibrosis (Kim et al, 2006;Meltzer & Noble, 2008).…”

Section: Discussionsupporting

confidence: 86%

A mechanistic review of silica-induced inhalation toxicity

Kawasaki

2015

Inhalation Toxicology

112

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Crystalline forms of silica have been proposed as positive control material for the toxicity test of inhaled particulate/fibrous matter, although mechanism of silica-induced inhalation toxicity has not yet been established. Inhalation exposure of α-quartz to rodents induces severe lung inflammation and fibrosis only after a certain period of latency, despite strong surface reactivity. The delayed occurrence of inhalation toxicity by α-quartz may be largely attributed to the sequestration of α-quartz particles by alternatively activated (M2) macrophages that express abundant levels of scavenger receptors but are relatively insensitive to inflammatory stimuli. When exposure to α-quartz continues, lung dust burden reaches a particle overload level, at which M2 macrophages cannot accommodate further quartz particles. Free quartz particles distributed in the interstitium interact with another subtype of macrophages, classically activated/inflammatory (M1) macrophages, which secrete various inflammatory cytokines, but silica-laden M1 macrophages initiate granuloma formation, which sequesters silica particles, too. Furthermore, the ability of M2 macrophages to clear foreign matter, particularly bacterial endotoxins [lipopolysaccharides (LPS)], may decrease due to α-quartz cytotoxicity. When LPS concentration in the lung reaches a certain level, LPS primes M1 macrophages to prepare for interleukin-1β production in response to α-quartz and also stimulates M1 macrophages and plasmacytoid dendritic cells (pDCs) to produce tumor necrosis factor (TNF)-α and interferon (IFN)-β, respectively. Besides, IFN-β may enhance TNF-α production in LPS-stimulated M1 macrophages. The elevated levels of inflammatory cytokines produce progressive lung inflammation and fibrosis.

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Section: Discussionsupporting

confidence: 86%

A mechanistic review of silica-induced inhalation toxicity

Kawasaki

2015

Inhalation Toxicology

112

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“…Bleomycin is metabolized in the lung, leading to a decrease in neutrophilic inflammation and a fibrotic response that spontaneously resolves after 2 to 3 months (Walters and Kleeberger, 2008). In the silica model, the stimulating crystals are not cleared from the lung, leading to ongoing inflammation, granuloma formation, and progressive fibrosis (Callis et al, 1985;Brass et al, 2012). In our study, Total lung collagen was determined by Sircol assay in lung homogenate (H).…”

Section: Discussionmentioning

confidence: 72%

Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis

Wollin

Maillet

Quesniaux

et al. 2014

J Pharmacol Exp Ther

537

447

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The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis. To explore its mode of action, nintedanib was tested in human lung fibroblasts and mouse models of lung fibrosis. Human lung fibroblasts expressing platelet-derived growth factor (PDGF) receptor-a and -b were stimulated with platelet-derived growth factor BB (homodimer) (PDGF-BB). Receptor activation was assessed by autophosphorylation and cell proliferation by bromodeoxyuridine incorporation. Transforming growth factor b (TGFb)-induced fibroblast to myofibroblast transformation was determined by a-smooth muscle actin (aSMA) mRNA analysis. Lung fibrosis was induced in mice by intratracheal bleomycin or silica particle administration. Nintedanib was administered every day by gavage at 30, 60, or 100 mg/kg. Preventive nintedanib treatment regimen started on the day that bleomycin was administered. Therapeutic treatment regimen started at various times after the induction of lung fibrosis. Bleomycin caused increased macrophages and lymphocytes in the bronchoalveolar lavage (BAL) and elevated interleukin-1b (IL-1b), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in lung tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced lung pathology additionally showed elevated BAL neutrophils, keratinocyte chemoattractant (KC) levels, and granuloma formation. Nintedanib inhibited PDGF receptor activation, fibroblast proliferation, and fibroblast to myofibroblast transformation. Nintedanib significantly reduced BAL lymphocytes and neutrophils but not macrophages. Furthermore, interleukin-1b, KC, TIMP-1, and lung collagen were significantly reduced. Histologic analysis showed significantly diminished lung inflammation, granuloma formation, and fibrosis. The therapeutic effect was dependent on treatment start and duration. Nintedanib inhibited receptor tyrosine kinase activation and the proliferation and transformation of human lung fibroblasts and showed antifibrotic and anti-inflammatory activity in two animal models of pulmonary fibrosis. These results suggest that nintedanib may impact the progressive course of fibrotic lung diseases such as idiopathic pulmonary fibrosis.

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“…Silica-induced lung inflammation and granuloma formation are reduced by the administration of TNF inhibitors or in animals deficient in TNF-α receptors [14]–[16]. The exacerbation of innate immune responses by repeated LPS exposure also amplifies the granulomatous response to silica in mice [17]. Finally, systemic inhibition of NF-kappa B activation with a pharmacological inhibitor decreases the severity of experimental silicosis [18].…”

Section: Introductionmentioning

confidence: 99%

Uncoupling between Inflammatory and Fibrotic Responses to Silica: Evidence from MyD88 Knockout Mice

Yakoub

Devosse

et al. 2014

PLoS ONE

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The exact implication of innate immunity in granuloma formation and irreversible lung fibrosis remains to be determined. In this study, we examined the lung inflammatory and fibrotic responses to silica in MyD88-knockout (KO) mice. In comparison to wild-type (WT) mice, we found that MyD88-KO animals developed attenuated lung inflammation, neutrophil accumulation and IL-1β release in response to silica. Granuloma formation was also less pronounced in MyD88-KO mice after silica. This limited inflammatory response was not accompanied by a concomitant attenuation of lung collagen accumulation after silica. Histological analyses revealed that while pulmonary fibrosis was localized in granulomas in WT animals, it was diffusely distributed throughout the parenchyma in MyD88-KO mice. Robust collagen accumulation was also observed in mice KO for several other components of innate immunity (IL-1R, IL-1, ASC, NALP3, IL-18R, IL-33R, TRIF, and TLR2-3-4,). We additionally show that pulmonary fibrosis in MyD88-KO mice was associated with the accumulation of pro-fibrotic regulatory T lymphocytes (T regs) and pro-fibrotic cytokine expression (TGF-β, IL-10 and PDGF-B), not with T helper (Th) 17 cell influx. Our findings indicate that the activation of MyD88-related innate immunity is central in the establishment of particle-induced lung inflammatory and granuloma responses. The development of lung fibrosis appears uncoupled from inflammation and may be orchestrated by a T reg-associated pathway.

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Innate Immune Activation by Inhaled Lipopolysaccharide, Independent of Oxidative Stress, Exacerbates Silica-Induced Pulmonary Fibrosis in Mice

Cited by 14 publications

References 43 publications

A mechanistic review of silica-induced inhalation toxicity

A mechanistic review of silica-induced inhalation toxicity

Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis

Uncoupling between Inflammatory and Fibrotic Responses to Silica: Evidence from MyD88 Knockout Mice

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