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Fialkow, Léa; Filho, Luciano Fochesatto; Bozzetti, Mary Clarisse; Milani, Adriana Rosa; Filho, Édison Moraes Rodrigues; Ladniuk, Roberta M; Pierozan, Paula; Moura, Rafaela Moraes de; Prolla, João Carlos; Vachon, Éric; Downey, Gregory P.

doi:10.1186/cc5090

Cited by 117 publications

(61 citation statements)

References 68 publications

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“…Moreover, blockade of PMN migration into the lung diminishes tissue damage and favors survival of mice infected with this organism (28). As PMN apoptosis is essential to limit tissue injury, particularly in the lung (61), and we demonstrate here that F. tularensis profoundly inhibits this process, our findings support a model in which neutrophils play a prominent role in dysregulation of the inflammatory response during tularemia. The effects of delayed PMN apoptosis can be exacerbated by defects in corpse removal by macrophages, which increases the probability that dying neutrophils will progress to secondary necrosis with spilling of toxic cell contents and alarmins that amplify inflammation and tissue damage (6–8, 60, 62).…”

Section: Discussionsupporting

confidence: 83%

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Francisella tularensis Inhibits the Intrinsic and Extrinsic Pathways To Delay Constitutive Apoptosis and Prolong Human Neutrophil Lifespan

Schwartz

Barker

Kaufman

et al. 2012

The Journal of Immunology

185

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Francisella tularensis is a facultative intracellular bacterium that infects many cell types including neutrophils. We demonstrated previously that F. tularensis inhibits NADPH oxidase assembly and activity and then escapes the phagosome to the cytosol, but effects on other aspects of neutrophil function are unknown. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis typically accelerates this process. We now demonstrate that F. tularensis significantly inhibited neutrophil apoptosis as indicated by morphological analysis as well as Annexin V and TUNEL staining. Thus, ~80% of infected neutrophils remained viable at 48 h as compared with ~50% of control cells, and ~40% of neutrophils that ingested opsonized zymosan. In keeping with this, processing and activation of procaspases-8, -9 and -3 were markedly diminished and delayed. F. tularensis also significantly impaired apoptosis triggered by Fas crosslinking. Of note, these effects were dose-dependent and could be conferred by either intracellular or extracellular live bacteria, but not by formalin-killed organisms or isolated LPS and capsule, and were not affected by disruption of wbtA2 or FTT1236/FTL0708, genes required for LPS O-antigen and capsule biosynthesis. In summary, we demonstrate for the first time that F. tularensis profoundly impairs constitutive neutrophil apoptosis via effects on the intrinsic and extrinsic pathways, and thereby define a new aspect of innate immune evasion by this organism. As defects in neutrophil turnover prevent resolution of inflammation, our findings also suggest a mechanism that may in part account for the neutrophil accumulation, granuloma formation and severe tissue damage that characterizes lethal pneumonic tularemia.

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Section: Discussionsupporting

confidence: 83%

“…During tularemia, efferocytosis is directly undermined by intramacrophage bacteria (63), and may be compromised further by local macrophage depletion (64). Moreover, end-stage tularemia is characterized by overwhelming sepsis (63, 65, 66), which is itself associated with decreased neutrophil apoptosis (61). Koedel et al .…”

Section: Discussionmentioning

confidence: 99%

Francisella tularensis Inhibits the Intrinsic and Extrinsic Pathways To Delay Constitutive Apoptosis and Prolong Human Neutrophil Lifespan

Schwartz

Barker

Kaufman

et al. 2012

The Journal of Immunology

185

View full text Add to dashboard Cite

show abstract

“…The anti-apoptotic effect of ARDS plasma on PMNs appears to be mediated through the GM-CSF receptor [67]. While the mean percentage of neutrophil apoptosis appears to be lower in sepsis-induced ARDS when compared with uncomplicated sepsis [68], in infants receiving extracorporeal membrane oxygenation for severe respiratory failure, survivors had proapoptotic BALF to neutrophils compared with nonsurvivors [69]. These differences, however, may well be a reflection of differences in the pro/anti-apoptotic milieu of the blood versus the alveolus.…”

Section: Pmn Apoptosis and Clearancementioning

confidence: 99%

Pathogenesis of indirect (secondary) acute lung injury

Perl

Lomas-Neira

Venet

et al. 2011

Expert Review of Respiratory Medicine

148

121

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At present, therapeutic interventions to treat acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remain largely limited to lung-protective strategies, as no real molecular–pathophysiologic-driven therapeutic intervention has yet become available. This is in part the result of the heterogeneous nature of the etiological processes that contribute to the state of ALI/ARDS. This article sets out to understand the development of ALI resulting from indirect pulmonary insults, such as extrapulmonary sepsis and trauma, shock, burn injury or mass transfusion, as opposed to direct pulmonary challenges, such as pneumonia, aspiration or lung contusion. Here, we consider not only the experimental and clinical data concerning the roles of various immune (neutrophil, macrophage, lymphocyte and dendritic) as well as nonimmune (epithelial and endothelial) cells in orchestrating the development of ALI resulting from indirect pulmonary stimuli, but also how these cell populations might be targeted therapeutically.

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“…In animal models, failure in this apoptosis, due to deficiency in either TNF-related apoptosis-inducing ligand (TRAIL) or caspase-1, has been shown to lead to an enhanced inflammatory response (5, 6), and strategies to pharmacologically induce apoptosis promote enhanced resolution of ALI responses (7). Neutrophils from patients with ARDS have been shown to exhibit lowered levels of apoptosis than normal (8), while neutrophil numbers were lower in patients who survived ARDS versus those who did not (9). However, the processes that regulate the numbers of neutrophils or induce their apoptotic clearance remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 Limits the Onset of Innate Lung Inflammation by Promoting Mast Cell–Derived IL-6

Ganeshan

Johnston

Bryce

2013

The Journal of Immunology

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TGFβ1 is an important suppressive mediator of inflammation but can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung and TGFβ1 has been suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury (ALI), we demonstrate that TGFβ1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis, rather than less migration. We demonstrate that TGFβ1 does not directly regulate neutrophil apoptosis, but instead functions through IL-6 to promote neutrophil clearance. Recombinant IL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in brochoalveolar lavage fluid while IL-6 is rapidly elevated following LPS-induced injury. Mast cells are a critical source of the IL-6, as mast cell deficient mice exhibit increased neutrophil numbers that is reduced by reconstitution with WT, but not IL-6−/−, mast cells. While IL-6 diminishes neutrophilia in mast cell-deficient mice, TGFβ1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGFβ1, likely derived from resident Tregs, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.

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Cited by 117 publications

References 68 publications

Francisella tularensis Inhibits the Intrinsic and Extrinsic Pathways To Delay Constitutive Apoptosis and Prolong Human Neutrophil Lifespan

Francisella tularensis Inhibits the Intrinsic and Extrinsic Pathways To Delay Constitutive Apoptosis and Prolong Human Neutrophil Lifespan

Pathogenesis of indirect (secondary) acute lung injury

TGF-β1 Limits the Onset of Innate Lung Inflammation by Promoting Mast Cell–Derived IL-6

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