Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor β

Wesselkamper, Scott C.; Case, Lisa M.; Henning, Lisa N.; Borchers, Michael T.; Tichelaar, Jay W.; Mason, John M.; Dragin, Nadine; Medvedovic, Mario; Sartor, Maureen A.; Tomlinson, Craig R.; Leikauf, George D.

doi:10.1164/rccm.200502-286oc

Cited by 71 publications

(58 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 TGF-b1 is a multifunctional cytokine that has a vital role in modifying lung permeability, epithelial ion transport, fibrinolysis, ECM deposition and surfactant homeostasis and can induce the cytoskeletal reorganization observed in EMT. 11 A previous study of patients with lung fibrogenesis revealed that engaging the avb6 integrin of epithelial cells to fibronectin may trigger the activation and production of TGF-b1. 10 Moreover, epithelial cells can promote lung fibrogenesis by acquiring a mesenchymal phenotype through the mediation of TGF-b1.…”

Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-b1(TGF-b1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (V T ) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-V T (6 ml/kg) or high-V T (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-V T mechanical ventilation increased microvascular permeability, PAI-1 and TGF-b1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of a-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (Po0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (Po0.05). Our data suggest that high-V T mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. Acute respiratory distress syndrome (ARDS) is a disorder of acute respiratory failure and manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia. 1,2 Mechanical ventilation with high-tidal volume (V T ) causes severe lung injury (ventilator-induced lung injury (VILI)) characterized by an initial inhomogeneous inflammatory reaction or epithelial injury that is followed by a fibroproliferative phase with fibroblast proliferation. 3-8 Epithelialmesenchymal transition (EMT) is the differentiation of epithelial cells into myofibroblast-like cells, which contributes to the fibroproliferative phase. 3-8 Upregulating Src, the plasminogen activator inhibitor-1 (PAI-1), and the transforming growth factor-b1(TGF-b1) has recently been demonstrated to regulate EMT. 9-14 However, the mechanisms regulating the interactions between mechanical ventilation and EMT remain unclear.PAI-1, a member of the serine protease inhibitor (serpin) gene family, rapidly inhibits both the urokinase-type plasminogen activator and the tissue-type plasminogen activator (tPA). 15 Mice with homozygous deletion of PAI-1 were relatively protected from bleomycin-induced pulmonary fibrogenesis, whereas overexpression of PAI-1 enhanced pulmonary fibrogenesis. 9 As a primary profibrogenic cytokine...

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…SEMA7A polymorphisms are associated with abnormal bone mineral density in Korean women (72). During acute lung injury, TGFB1 can increase endothelial and epithelial permeability (73)(74)(75), and the inhibition of TGFB1 can diminish lung injury (66,(76)(77)(78). SEMA7A can mediate AKT phosphorylation (71), which is …”

Section: Discussionmentioning

confidence: 99%

“…During gross pathologic observations at death, the lung surface appeared red from hemorrhaging and coagulation consistent with severe lung injury (66). The mean survival time was distributed continuously among murine strains (supportive of a complex trait), with the polar strains varying by approximately 5-fold from 7.6 6 0.8 (mean 6 SEM) hours (PWD/PhJ) to 38.1 6 0.5 hours (NON/ShiLtJ) ( Figure 1A).…”

Section: Haplotype Mapping Of Survival Times In 40 Murine Strainsmentioning

confidence: 92%

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

Leikauf

Pope-Varsalona

Concel

et al. 2012

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using > 10% allelic frequency and > 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4.

show abstract

“…For example, the inhalation of nickelcontaining substances has been shown to be linked to a rise in Transforming Growth Factor Beta (TGF-B) levels, yielding morphological changes in the lung tissue. These changes to the lung tissue may also result in respiratory failure [11] . Inflammation of the lung tissues as a result of inhaled toxins is also considered to be a lung cancer risk factor [4] .…”

Section: Introductionmentioning

confidence: 99%

Indications of Potential Toxic/Mutagenic Effects of World Trade Center Dust on Human Lung Cell Cultures

Lambroussis¹,

Soares²,

Pérez³

et al. 2009

OnLine J. of Biological Sciences

View full text Add to dashboard Cite

Problem statement: Respiratory complications have been linked with exposure to dust particulates after the tragedy of September 11th, 2001 at the World Trade Center (WTC) site. Approach: The purpose of these experiments was to investigate the extent of cellular damage resulting from WTC dust exposure. Results: This research project was conducted with human lung fibroblast cells exposed to WTC dust. To determine if cell proliferation levels were affected, cultured cells were exposed to WTC dust at various concentrations in simulated physiological stress environments via decreased serum levels. Results indicated that cell proliferation levels decreased as WTC dust concentrations increased. This pattern persisted regardless of serum level. The serum concentrations used were 10% Fetal Bovine Serum (FBS), which represented a non-stressed system, with 2.5 and 1% FBS concentrations used to simulate stressed environments. Assessment for apoptosis, programmed cell death, resulted in higher than baseline levels in cells exposed to WTC dust in both MRC-5 and WI-38 human lung fibroblasts. Conclusion/Recommendations: In summary, results showed that exposure to WTC dust led to decreased cell proliferation and increased apoptosis levels. These findings evidence need for future research regarding mutagenic properties of World Trade Center dust.

show abstract

Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor β

Cited by 71 publications

References 87 publications

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

Indications of Potential Toxic/Mutagenic Effects of World Trade Center Dust on Human Lung Cell Cultures

Contact Info

Product

Resources

About