Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice

Russo, Remo C.; Garcia, Cristiana C.; Barcelos, Lucíola da Silva; Rachid, Milene Alvarenga; Guabiraba, Rodrigo; Roffê, Ester; Souza, Adriano Lopes de; Sousa, Lirlândia P.; Mirolo, Massimiliano; Doni, Andrea; Cassali, Geovanni Dantas; Pinho, Vanessa; Locati, Massimo; Teixeira, Mauro Martins

doi:10.1189/jlb.0610346

Cited by 58 publications

(62 citation statements)

References 60 publications

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“…It is not known if restoration of fibroblast apoptosis can mitigate fibrotic lung disease in vivo, but several studies provide proof of principal that modulation of signaling pathways involved in fibroblast resistance to apoptosis can attenuate fibrogenesis in murine models (53)(54)(55)(56)(57). Our findings suggest that XIAP antagonists may have therapeutic potential in disease processes characterized by fibroblast accumulation and fibrosis, although it will be critical to determine the impact of these antagonists on other cell populations before translating this strategy to patient care.…”

Section: Discussionmentioning

confidence: 83%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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Section: Discussionmentioning

confidence: 83%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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“…BAL was collected for leukocyte counting as well as protein and nitrite quantification. 15 All experimental groups included N ! 5.…”

Section: Methodsmentioning

confidence: 99%

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Marques¹,

Amaral²,

Pires³

et al. 2012

Hepatology

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280

269

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Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9 2/2 mice). Conclusion: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.

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“…The product of Nitric Oxide oxidation, nitrite, was measured by adding 100 µL of BALF and 100 µL of Griess reagent (1% sulfanilamide and 0.1% naphthylethylenediamide in 5% phosphoric acid) and comparing to the absorbance at 550 nm to a standard curve of sodium nitrite [50].…”

Section: Methodsmentioning

confidence: 99%

Protective Immunity and Safety of a Genetically Modified Influenza Virus Vaccine

et al. 2014

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Recombinant influenza viruses are promising viral platforms to be used as antigen delivery vectors. To this aim, one of the most promising approaches consists of generating recombinant viruses harboring partially truncated neuraminidase (NA) segments. To date, all studies have pointed to safety and usefulness of this viral platform. However, some aspects of the inflammatory and immune responses triggered by those recombinant viruses and their safety to immunocompromised hosts remained to be elucidated. In the present study, we generated a recombinant influenza virus harboring a truncated NA segment (vNA-Δ) and evaluated the innate and inflammatory responses and the safety of this recombinant virus in wild type or knock-out (KO) mice with impaired innate (Myd88 -/-) or acquired (RAG -/-) immune responses. Infection using truncated neuraminidase influenza virus was harmless regarding lung and systemic inflammatory response in wild type mice and was highly attenuated in KO mice. We also demonstrated that vNA-Δ infection does not induce unbalanced cytokine production that strongly contributes to lung damage in infected mice. In addition, the recombinant influenza virus was able to trigger both local and systemic virus-specific humoral and CD8+ T cellular immune responses which protected immunized mice against the challenge with a lethal dose of homologous A/PR8/34 influenza virus. Taken together, our findings suggest and reinforce the safety of using NA deleted influenza viruses as antigen delivery vectors against human or veterinary pathogens.

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Phosphoinositide 3-kinase γ plays a critical role in bleomycin-induced pulmonary inflammation and fibrosis in mice

Cited by 58 publications

References 60 publications

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Protective Immunity and Safety of a Genetically Modified Influenza Virus Vaccine

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