Agonists of Toll-like Receptors 2 and 4 Activate Airway Smooth Muscle via Mononuclear Leukocytes

Morris, George E.; Whyte, Moira K. B.; Martin, Gillian F.; Jose, Peter J.; Dower, Steven K.; Sabroe, Ian

doi:10.1164/rccm.200403-406oc

Cited by 80 publications

(121 citation statements)

References 56 publications

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“…LPS exposure induced increased diffuse expression in multiple cell types in the lung. Similar diffuse localization has been shown in the adult human lung (23,26,27). The resolution of in situ hybridization does not allow for localization of the signal to specific cells.…”

Section: Discussionmentioning

confidence: 64%

Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

et al. 2008

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Toll-like receptors (TLRs) are pattern recognition molecules that initiate innate immune responses. Intra-amniotic exposure of fetal sheep to pro-inflammatory stimuli causes pulmonary inflammation and induced lung maturation. We examined TLR ontogeny and fetal lung responsiveness to three different TLR agonists. We cloned ovine TLRs 2, 3, and 4 and found 83-88% homology between these ovine and human TLRs. Lung TLR2 and 4 mRNAs increased throughout late gestation to 50% of adult level in the term newborn lamb. Doses of 10 mg of PAMCysK 4 (TLR2 agonist), poly I:C dsRNA (TLR3 agonist), or E. coli O55:B5 lipopoysaccharide (LPS) (TLR4 agonist) were given by intra-amniotic injection 2 d or 7 d before operative delivery of preterm lambs at 123 d (n ϭ 4 -7/group). The TLR4 agonist induced lung inflammation and maturation, whereas the TLR2 agonist gave less consistent responses. Intra-amniotic LPS increased TLR2 mRNA expression primarily in the inflammatory cells and TLR4 mRNA diffusely in multiple cell types. The TLR3 agonist had no effects, and TLR3 mRNA in the fetal lung did not change after LPS exposure. We conclude that TLR2 and TLR4 mRNAs increase through gestation and expression of TLR2

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Section: Discussionmentioning

confidence: 64%

Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

et al. 2008

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“…Generally, expression of PRRs by immune cells such as M1 macrophages serves a protective role following infection. Structural cells such as type II alveolar epithelial cells (47), airway smooth muscle cells (48), airway epithelial cells (49), and fibroblasts express TLRs, including TLR2, TLR3, TLR4, and TLR9, and are activated by specific TLR ligands. Less is known about the expression and activation of other PRRs in these cell types.…”

Section: From Pathogens To the Chronic Inflammatory Response And Pathmentioning

confidence: 99%

Infectious disease, the innate immune response, and fibrosis

Meneghin¹,

Hogaboam²

2007

J. Clin. Invest.

178

163

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The unrelenting and destructive progression of most fibrotic responses in the pulmonary, cardiovascular, integumentary, and alimentary systems remains a major medical challenge for which therapies are desperately needed. The pathophysiology of fibrosis remains an enigma, but considerable research and debate surrounds the question of whether chronic inflammation is the key driver of unrestrained wound healing (i.e., the fibrotic response) in these and other organ systems. This Review describes how infectious pathogens, chronic inflammation, and unrestrained fibroproliferation are likely to be part of a dynamic, unrelenting process propelling human fibrotic diseases.

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“…Furthermore, urban particulate matter has been shown to cause the release of monocytes from the bone marrow (17, 23). We have previously shown that effective inflammatory responses to bacterial-derived stimuli are mediated by cooperative signaling between monocytes and tissue cells (31,32,39,50). The direct effects of DEP, with the production of proinflammatory cytokines and ROS in single cell types, are well established (4,9,25,27,29,37,43,49), but less is known about their actions in models of the cell networks that underpin inflammatory responses.…”

mentioning

confidence: 99%

Diesel exhaust particles override natural injury-limiting pathways in the lung

Chaudhuri

Paiva

Donaldson³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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tion of effective inflammation in the lung in response to environmental and microbial stimuli is dependent on cooperative signaling between leukocytes and lung tissue cells. We explored how these inflammatory networks are modulated by diesel exhaust particles (DEP) using cocultures of human monocytes with epithelial cells. Cocultures, or monoculture controls, were treated with DEP in the presence or absence of LPS or flagellin. Production of cytokines was explored by Western blotting and ELISA; cell signaling was analyzed by Western blotting. Here, we show that responses of epithelial cells to DEP are amplified by the presence of monocytes. DEP amplified the responses of cellular cocultures to very low doses of TLR agonists. In addition, in the presence of DEP, the responses induced by LPS or flagellin were less amenable to antagonism by the physiological IL-1 antagonist, IL-1ra. This was paralleled by the uncoupling of IL-1 production and release from monocytes, potentially attributable to an ability of DEP to sequester or degrade extracellular ATP. These data describe a model of inflammation where DEP amplifies responses to low concentrations of microbial agonists and alters the nature of the inflammatory milieu induced by TLR agonists.cocultures; inflammation; interleukin-1; Toll-like receptors ENVIRONMENTAL EXPOSURE to microbial products through the inhalation of bacterial fragments, such as LPS, has long been associated with exacerbations of airway disease, and levels of LPS within the environment can correlate with severity of asthma (30,38). Asthma and COPD are commonly exacerbated by bacterial and viral infections (3, 24) that can often coexist and synergize with pollutant exposure (8, 46). Inhalation of small particulate matter is also a major cause of airway inflammation, and rising air pollution levels are associated with elevated mortality and increased hospital admissions in individuals with respiratory diseases such as asthma and COPD (2, 10, 45).Diesel exhaust particles (DEP) are the major particulate matter of air pollution and comprise a nanoparticular carbonaceous core, multiple organic components such as polyaromatic hydrocarbons (PAH), transition metals, and adsorbed materials such as pollen and dust. Their small size (5-20 nm; 100-nm aggregates) means that they are often denoted nanoparticles and favors their deposition in the lung (7, 11). Acute and chronic inhalation of DEP in healthy individuals, and those with preexisting respiratory disease, results in respiratory toxicity with consequent development of lung edema, infiltration of polymorphonuclear leukocytes, and the production of proinflammatory cytokines and reactive oxygen species (ROS) (5,36,44,47).The active inflammation that occurs in asthma and COPD leads to the recruitment of monocytes to the alveolar wall (28). Furthermore, urban particulate matter has been shown to cause the release of monocytes from the bone marrow (17, 23). We have previously shown that effective inflammatory responses to bacterial-derived stimuli are media...

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Agonists of Toll-like Receptors 2 and 4 Activate Airway Smooth Muscle via Mononuclear Leukocytes

Abstract: These data indicate that potent amplification of inflammation induced by TLR agonists, such as LPS, may be achieved by cooperativity between airway smooth muscle and leukocytes involved in immune surveillance or inflammation.

Cited by 80 publications

References 56 publications

Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

Toll-Like Receptors and Agonist Responses in the Developing Fetal Sheep Lung

Infectious disease, the innate immune response, and fibrosis

Diesel exhaust particles override natural injury-limiting pathways in the lung

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