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Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis

Authors:
Emmett Mcgrath at University of Plymouth
Emmett Mcgrath
Allan Lawrie at Imperial College London
Allan Lawrie
Helen Maria Marriott at The University of Sheffield
Helen Maria Marriott
Paul F Mercer at University College London
Paul F Mercer
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Abstract and Figures

The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF. TRAIL(-/-) and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA. TRAIL(-/-) mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19±0.8 wild type vs 11.5±5.4×10(4) TRAIL(-/-), p<0.0001), reduced neutrophil apoptosis (5.42±1.6% wild type vs 2.47±0.5% TRAIL(-/-), p=0.0003) and increased collagen (3.45±0.2 wild type vs 5.8±1.3 mg TRAIL(-/-), p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild-type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1±9.6 controls vs 32.3±7.2 pg/ml patients with IPF, p=0.002). These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF.
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mmunohistochemical localisation of tumour necrosis factor- related apoptosis-inducing ligand (TRAIL) in human lung specimens. Immunostaining for TRAIL on representative lung tissue sections from human lung material. (A) and (B) Intense immunostaining for TRAIL in control lung was associated with macrophages and alveolar epithelium. Representative images are shown from lung sections of three individuals. (C e F) Analysis of lung tissue from patients with idiopathic pulmonary fibrosis. Representative images are shown from lung sections of five individuals. (C, D) Areas of lung with relatively normal architecture showed TRAIL staining similar to that from control lung samples whereas matched samples from fibrotic areas of the same individuals (E, F) demonstrated almost no positive immunostaining for TRAIL. Scale bars for panels (A), (C) and (E) represent 100 m m and for (B), (D) and (F) 50 m m.
mmunohistochemical localisation of tumour necrosis factor- related apoptosis-inducing ligand (TRAIL) in human lung specimens. Immunostaining for TRAIL on representative lung tissue sections from human lung material. (A) and (B) Intense immunostaining for TRAIL in control lung was associated with macrophages and alveolar epithelium. Representative images are shown from lung sections of three individuals. (C e F) Analysis of lung tissue from patients with idiopathic pulmonary fibrosis. Representative images are shown from lung sections of five individuals. (C, D) Areas of lung with relatively normal architecture showed TRAIL staining similar to that from control lung samples whereas matched samples from fibrotic areas of the same individuals (E, F) demonstrated almost no positive immunostaining for TRAIL. Scale bars for panels (A), (C) and (E) represent 100 m m and for (B), (D) and (F) 50 m m.
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Serum levels of tumour necrosis factor-related apoptosisinducing ligand (TRAIL) and its soluble receptor osteoprotegerin (OPG) in patients with idiopathic pulmonary fibrosis (IPF) and matched controls. Serum levels of (A) TRAIL and (B) OPG were measured by ELISA in patients with IPF and matched controls. Data was also expressed as (C) the ratio of OPG to TRAIL. TRAIL levels were significantly reduced in patients with IPF (**p¼0.002) and the OPG:TRAIL ratio correspondingly increased (*p¼0.033).
Serum levels of tumour necrosis factor-related apoptosisinducing ligand (TRAIL) and its soluble receptor osteoprotegerin (OPG) in patients with idiopathic pulmonary fibrosis (IPF) and matched controls. Serum levels of (A) TRAIL and (B) OPG were measured by ELISA in patients with IPF and matched controls. Data was also expressed as (C) the ratio of OPG to TRAIL. TRAIL levels were significantly reduced in patients with IPF (**p¼0.002) and the OPG:TRAIL ratio correspondingly increased (*p¼0.033).
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Serum levels of tumour necrosis factor-related apoptosisinducing ligand (TRAIL) correlate with TLco values. Serum TRAIL, measured at time of clinical presentation with idiopathic pulmonary fibrosis (IPF), was significantly correlated with TLco (% predicted) at time of diagnosis (r 2 ¼0.149, p¼0.046).
Serum levels of tumour necrosis factor-related apoptosisinducing ligand (TRAIL) correlate with TLco values. Serum TRAIL, measured at time of clinical presentation with idiopathic pulmonary fibrosis (IPF), was significantly correlated with TLco (% predicted) at time of diagnosis (r 2 ¼0.149, p¼0.046).
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Supplementary resources (2)

Supporting Statement
Data
April 2012
Emmet McGrath · Allan Lawrie · Helen Maria Marriott · Paul F Mercer · Moira K B Whyte
Supporting Statement
Data
April 2012
Emmet McGrath · Allan Lawrie · Helen Maria Marriott · Paul F Mercer · Moira K B Whyte
... In different states, TRAIL can play the dual roles of pro-in ammatory or antiin ammatory, pro-apoptosis or pro-cell proliferation [23][24][25].It was reported that the serum level of TRAIL in patients with SSc is signi cantly higher than that of the control group, and the serum TRAIL level of patients with lung involvement is positively correlated with the degree of lung lesions [16]. Many studies using mouse models of induced autoimmune diseases have shown that TRAIL has immunosuppressive functions [22,[26][27][28]. TRAIL de ciency exacerbates bleomycin-induced pulmonary brosis in mice [27]. ...
... Many studies using mouse models of induced autoimmune diseases have shown that TRAIL has immunosuppressive functions [22,[26][27][28]. TRAIL de ciency exacerbates bleomycin-induced pulmonary brosis in mice [27]. ...
Causal relationship between circulating cytokines and the risk of systemic sclerosis: A bidirectional Mendelian-randomization study
Preprint
Full-text available
  • Dec 2023
Objectives Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vasculopathy, and fibrosis. While cytokines likely contribute to SSc pathogenesis, it is unclear whether particular cytokines play a causal role. We aimed to investigate potential causal relationships between circulating cytokines and SSc using Mendelian randomization. Methods We conducted a bidirectional two-sample Mendelian randomization study using summary data from published genome-wide association studies of SSc (2,313 cases, 15,881 controls) and 43 cytokines (up to 31,781 individuals). Single nucleotide polymorphisms associated with cytokine levels were selected as instruments to proxy genetically determined circulating concentrations. Potential causal relationships between exposures and outcomes were investigated primarily through inverse variance weighted Mendelian randomization analysis. To substantiate the robustness of our findings, we additionally conducted several complementary sensitivity analyses utilizing alternative Mendelian randomization methods, including MR-Egger, weighted median, simple and weighted mode, and MR-PRESSO. Results Among the cytokines analyzed, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrated a significant causal association, whereby genetically predicted lower TRAIL levels increased SSc risk. Other circulating cytokines including TGF-β, IL-6, and PDGF, have no causal relationship with SSc. Conclusion Our findings implicate reduced circulating TRAIL level as a potential causal factor in SSc risk, providing novel insights into disease pathogenesis. These findings position TRAIL as a putative upstream regulator in SSc, suggesting modulation of the TRAIL signaling cascade may represent a promising therapeutic approach in SSc.
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... OPG was initially recognized for its role in bone turnover in which it prevents bone resorption and stimulates production of extracellular matrix in cartilage [18]. However, in recent years, an increasing number of studies have shown correlations between OPG and several fibrotic conditions including liver, vascular, cardiac, kidney and intestinal fibrosis [19][20][21][22][23][24][25][26][27][28][29]. This study, and our own previous studies [9,10] have now shown that this also appears to be the case for fibrosis in lung tissue and even wound healing. ...
Osteoprotegerin is an Early Marker of the Fibrotic Process and of Antifibrotic Treatment Responses in Ex Vivo Lung Fibrosis
Article
Full-text available
  • Apr 2024
  • LUNG
Background Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well. Methods Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker. Results OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFβ1 or IL13, and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFβ1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment. Conclusion OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.
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... OPG was initially recognized for its role in bone turnover in which it prevents bone resorption and stimulates production of extracellular matrix in cartilage [17]. However, in recent years, an increasing number of studies have shown correlations between OPG and several brotic conditions including liver, vascular, cardiac, kidney and intestinal brosis [18][19][20][21][22]. This study, and our own previous studies [9,10] have now shown that this also appears to be the case for brosis in lung tissue and even wound healing. ...
Osteoprotegerin is an early marker of the fibrotic process and of antifibrotic treatment responses in ex vivo lung fibrosis
Preprint
Full-text available
  • Jan 2024
Background Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well. Methods Here we used murine and human precision-cut lung slices to investigate the regulation of OPG in lung tissue to elucidate whether it tracks with (early) fibrosis development and responds to antifibrotic treatment to assess its potential use as a biomarker. Results OPG mRNA expression in murine lung slices was higher after treatment with profibrotic cytokines TGFβ1 or IL13 and closely correlated with Fn and PAI1 mRNA expression. More OPG protein was released from fibrotic human lung slices than from the control human slices and from TGFβ1 and IL13-stimulated murine lung slices compared to control murine slices. This OPG release was inhibited when murine slices were treated with pirfenidone or nintedanib. OPG release from human fibrotic lung slices was inhibited by pirfenidone treatment. Conclusion OPG can already be detected during the early stages of fibrosis development and responds, both in early- and late-stage fibrosis, to treatment with antifibrotic drugs currently on the market for lung fibrosis. Therefore, OPG should be further investigated as a potential biomarker for lung fibrosis and a potential surrogate marker for treatment effect.
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... However, the level of bleomycin-induced pulmonary fibrosis is reduced in FASdeficient lpr/lpr or FASL-deficient gld/gld mice [1021], but remains unchanged in mice treated with FAS-neutralizing agents [1022]. Likewise, contrasting findings support or refute a role for TNF [1023][1024][1025] and TRAIL [1026,1027] in the onset and resolution of pulmonary fibrosis after administration of bleomycin. TNF neutralization has been reported to attenuate and enhance interstitial pulmonary fibrosis induced by nitrogen mustard [1028] or rituximab [1029]. ...
Apoptotic cell death in disease—Current understanding of the NCCD 2023
Article
  • Apr 2023
  • CELL DEATH DIFFER
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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... Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has an important role in regulating the survival of immune cells, including neutrophils, and has been shown to be a potential marker of IPF. 77 As osteoprotegerin (OPG) is a decoy receptor of TRAIL, we measured its concentration to interpret the findings of TRAIL. MPO and TRAIL were purchased ...
Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT
Article
  • Jul 2021
Background Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. People with idiopathic pulmonary fibrosis have altered innate immunity and altered lung microbiota, with the bacterial burden relating to mortality. Two randomised controlled trials have demonstrated beneficial effects with co-trimoxazole (SEPTRIN ® ; Essential Generics Ltd, Egham, UK; Chemidex Generics Ltd, Egham, UK), with the suggestion of an improvement in rates of survival. Objectives To determine the clinical efficacy of co-trimoxazole in people with moderate to severe idiopathic pulmonary fibrosis. Design A Phase II, double-blind, placebo-controlled, parallel-group, randomised multicentre study. Setting UK specialist interstitial lung disease centres. Participants Patients who were randomised had idiopathic pulmonary fibrosis diagnosed by a multidisciplinary team. In addition, patients had significant breathlessness (i.e. a Medical Research Council Dyspnoea Scale score of > 1) and impaired lung function (i.e. a forced vital capacity of < 75% predicted). Patients could be taking licensed medication for idiopathic pulmonary fibrosis, but were excluded if they had significant comorbidities, including airflow obstruction. Intervention Oral co-trimoxazole, 960 mg twice per day (two 480-mg tablets twice per day), compared with placebo tablets (two tablets twice per day) for a median of 27 months (range 12–42 months). Otherwise, both trial groups had standard care. Main outcome measures The primary outcome was the time to death (all causes), transplant or first non-elective hospital admission. Secondary outcomes were the individual components of the primary end point and the number of respiratory-related events. Questionnaires (the King’s Brief Interstitial Lung Disease questionnaire; the Medical Research Council Dyspnoea Scale; EuroQol-5 Dimensions, five-level version; the Leicester Cough Questionnaire; and the Cough Symptom Score) and lung function tests (forced vital capacity and diffusing capacity for carbon monoxide) were undertaken at baseline and at 12 months. Results The trial randomised a total of 342 (295 male) patients (active treatment group, n = 170; placebo group, n = 172), using minimisation for hospital and receipt of licensed antifibrotic medication, from 39 UK hospitals. The patients had a mean (standard deviation) age of 71.3 years (7.47 years) and a mean forced vital capacity of 2.25 l (0.56 l). A total of 137 (40%) patients were taking pirfenidone (Esbriet, Roche Holding AG, Basel, Switzerland) and 116 (34%) were taking nintedanib (Ofev ® , Boehringer Ingelheim, Brackness, UK). There was one post-randomisation exclusion from the co-trimoxazole group, but no withdrawals. There was no difference in the time to event for the composite primary end point (co-trimoxazole: hazard ratio 1.2, 95% confidence interval 0.9 to 1.6; p = 0.319). Likewise, there was no difference in other event outcomes, lung function measurements or patient-reported outcomes, other than a beneficial effect on the total Leicester Cough Questionnaire score, the social domain of the Leicester Cough Questionnaire score and the chest domain of the King’s Brief Interstitial Lung Disease questionnaire in the adjusted analysis. The repeated-measures analysis showed a significant overall difference in Cough Symptom Score. There were significantly more reports of nausea, but fewer reports of diarrhoea, with co-trimoxazole; however, differences in frequency of hyperkalaemia, rash and headache were not significant. The limitations of the trial were that it was not possible to evaluate the lung microbiota, there were missing data for secondary end points and there was no health economic analysis. Conclusion These results suggest that co-trimoxazole does not reduce the likelihood of death or number of hospitalisations among people with idiopathic pulmonary fibrosis with moderate to severe idiopathic pulmonary fibrosis. Further work is required to evaluate the effect in subgroups of individuals with idiopathic pulmonary fibrosis or the effect of antibiotics with different antibacterial properties. Trial registration Current Controlled Trials ISRCTN17464641. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation ; Vol. 8, No. 9. See the NIHR Journals Library for further project information.
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... As RANKL induces degradation of extracellular matrix in bone, it may have similar effects in other tissues and neutralization of RANKL may prevent this. Deficiency in TRAIL was found to abrogate lung injury and fibrosis in bleomycin-treated mice and lower levels of TRAIL were found in patients with IPF [97]. It is suggested that excessive myofibroblast activation and extracellular matrix production is prevented by TRAIL-induced apoptosis of myofibroblasts. ...
The potential of biomarkers of fibrosis in chronic lung allograft dysfunction
Article
Full-text available
  • May 2021
  • Transplant Rev
Chronic lung allograft dysfunction (CLAD) is the major long-term cause of morbidity and mortality after lung transplantation. Both bronchiolitis obliterans syndrome and restrictive lung allograft syndrome, two main types of CLAD, lead to fibrosis in either the small airways or alveoli and pleura. Pathological pathways in CLAD and other types of fibrosis, for example idiopathic pulmonary fibrosis, are assumed to overlap and therefore fibrosis biomarkers could aid in the early detection of CLAD. These biomarkers could help to differentiate between different phenotypes of CLAD and could, in comparison to biomarkers of inflammation, possibly distinguish an infectious event from CLAD when a decline in lung function is present. This review gives an overview of known CLAD specific biomarkers, describes new promising fibrosis biomarkers currently investigated in other types of fibrosis, and discusses the possible use of these fibrosis biomarkers for CLAD.
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... There has been an association between the upregulation TRAIL and the promotion of apoptosis of airway epithelial cells, allergic airways disease, airway hyperresponsiveness, pulmonary inflammation and mucus hypersecretion [13][14][15]. Conversely, it has also been found that down-regulation of TRAIL or TRAIL deficiency is associated with idiopathic pulmonary fibrosis (IPF) [16]. Therefore, it is thought that TRAIL may have a "divergent" role when it comes to its association with lung diseases [17]. ...
Lung function is associated with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) levels in school-aged children
Article
Full-text available
  • Jan 2021
  • RESP MED
Background Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. A complex relationship exists between TRAIL and the lung where both elevated TRAIL and TRAIL deficiency are associated with lung impairment. In neonatal mice, TRAIL is thought to translate respiratory infections into chronic lung disease but the association between TRAIL and lung function in childhood has not been assessed. Aim To assess the cross-sectional relationship between TRAIL levels and lung function in school-aged children. Methods The study cohort consisted of 170 school-aged children attending four schools in Malmö, Sweden. Lung volumes, impulse oscillometry (IOS) and serum TRAIL were measured for all children. Linear regression was used to assess changes in lung function per 1-SD increase in TRAIL. General linear models were used to assess mean lung function by tertiles (T) of TRAIL. Results Mean age was 9.9 years (±0.6). A 1-SD increase in TRAIL was associated with lower values of FEV1 and FEV1/VC (change in FEV1 (L) and FEV1/VC ratio: −0.047, p-value 0.002, and −0.011, p-value 0.020, respectively) and higher values of lung resistance (change in R5 and R20 (kPa/(L/s)): 0.035, p-value <0.001 and 0.027, p-value 0.004, respectively). These associations remained significant after excluding children with pre-existing lung disease. Higher TRAIL levels were associated with more negative values for X5 in general linear models (Mean X5 (kPa/(L/s)) in T1 (low TRAIL): −0.193 vs T3 (high TRAIL): −0.216, p-value 0.026). Conclusions High TRAIL levels are significantly associated with markers of pulmonary airflow obstruction in school-aged children.
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Elevated soluble death receptor 5 can predict poor prognosis in patients with acute respiratory distress syndrome
Article
  • Jul 2022
Background: : The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 5 (DR5), participate in pulmonary cell apoptosis. This study aimed to investigate the clinical value of soluble DR5 and TRAIL for prognosis assessment in acute respiratory distress syndrome (ARDS). Research design and methods: : Serum and bronchoalveolar lavage fluid (BALF) samples were collected from ARDS patients and controls. Patients were followed-up until death or discharge. Soluble DR5, TRAIL, TNF-α, soluble receptor for advanced glycation end-products (sRAGE), and albumin levels were measured using the Magnetic Luminex or enzyme-linked immunosorbent assays. Data were analyzed according to their distribution and statistical purpose. Results: : Serum and BALF DR5 levels were elevated in patients with ARDS; TRAIL elevation and reduction was observed in BALF and serum, respectively. Serum DR5 was higher in non-survivors compared to survivors. Serum DR5 was positively correlated with serum TNF-α and critical illness scores and negatively correlated with serum TRAIL. Serum and BALF DR5 was positively correlated with the alveolar epithelial cell damage (sRAGE) and lung fluid leakage indicators. Serum DR5 exhibited potential for predicting mortality in patients with ARDS. Conclusions: : Serum soluble DR5 elevation, a valuable prognosis predictor in ARDS, may be associated with alveolar epithelial cell apoptosis.
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The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure
Article
  • Apr 2022
  • CIRC RES
Pulmonary hypertension (PH) describes heterogeneous population of patients with a mean pulmonary arterial pressure >20 mm Hg. Rarely, PH presents as a primary disorder but is more commonly part of a complex phenotype associated with comorbidities. Regardless of the cause, PH reduces life expectancy and impacts quality of life. The current clinical classification divides PH into 1 of 5 diagnostic groups to assign treatment. There are currently no pharmacological cures for any form of PH. Animal models are essential to help decipher the molecular mechanisms underlying the disease, to assign genotype-phenotype relationships to help identify new therapeutic targets, and for clinical translation to assess the mechanism of action and putative efficacy of new therapies. However, limitations inherent of all animal models of disease limit the ability of any single model to fully recapitulate complex human disease. Within the PH community, we are often critical of animal models due to the perceived low success upon clinical translation of new drugs. In this review, we describe the characteristics, advantages, and disadvantages of existing animal models developed to gain insight into the molecular and pathological mechanisms and test new therapeutics, focusing on adult forms of PH from groups 1 to 3. We also discuss areas of improvement for animal models with approaches combining several hits to better reflect the clinical situation and elevate their translational value.
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Targeting of keloid with TRAIL and TRAIL-R2/DR5
Article
  • Jan 2020
Keloid is a common and frequently-occurring disease in plastic surgery, and its ugly appearance and itching symptoms bring mental and life pain to patients. However, the clinical treatment of keloid, such as drug injection treatment, surgical resection, cryotherapy, laser treatment and other therapeutic effects are poor. Since the discovery of tumor necrosis factor related apoptosis inducing ligand (TRAIL) in 1995, its selective apoptosis on tumor cells makes it have a great prospect in the targeted treatment of tumor. In recent years, it has been found that the formation of keloid is related to the imbalance of apoptosis of fibroblasts in scar and the binding of TRAI to its receptor mediates the apoptosis of fibroblasts. Therefore, the use of TRAIL and TRAIL-R2/death receptor 5 (DR5) in the treatment of keloid has become a hot research topic.In this paper, the present situation, mechanism and development prospect of TRAIL and TRAIL-R2/DR5 targeted treatment of keloid were reviewed, which provided a reference for promoting the development of keloid treatment.
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TNF-related apoptosis-inducing ligand (TRAIL) regulates inflammatory neutrophil apoptosis and enhances resolution of inflammation
Article
Full-text available
  • May 2011
  • J LEUKOCYTE BIOL
Novel therapeutics targeting neutrophilic inflammation are a major unmet clinical need in acute and chronic inflammation. The timely induction of neutrophil apoptosis is critical for inflammation resolution, and it is thought that acceleration of apoptosis may facilitate resolution at inflammatory sites. We previously demonstrated that a death receptor ligand, TRAIL, accelerates neutrophil apoptosis in vitro. We examined the role of TRAIL in neutrophil-dominant inflammation in WT and TRAIL-deficient mice. TRAIL deficiency did not alter constitutive neutrophil apoptosis, whereas exogenous TRAIL accelerated apoptosis of murine peripheral blood neutrophils. We compared TRAIL-deficient and WT mice in two independent models of neutrophilic inflammation: bacterial LPS-induced acute lung injury and zymosan-induced peritonitis. In both models, TRAIL-deficient mice had an enhanced inflammatory response with increased neutrophil numbers and reduced neutrophil apoptosis. Correction of TRAIL deficiency and supraphysiological TRAIL signaling using exogenous protein enhanced neutrophil apoptosis and reduced neutrophil numbers in both inflammatory models with no evidence of effects on other cell types. These data indicate the potential therapeutic benefit of TRAIL in neutrophilic inflammation.
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Gelsolin expression is necessary for the development of modeled pulmonary inflammation and fibrosis
Article
Full-text available
  • Mar 2009
  • THORAX
Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation. To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts. Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis. Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis, while the caspase-3-mediated gelsolin fragmentation was shown to be an apoptotic effector mechanism in disease pathogenesis and a marker of lung injury.
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TRAIL Agonists on Clinical Trials for Cancer Therapy: The Promises and the Challenges
Article
Full-text available
  • Feb 2009
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is normally expressed in the human immune system and plays a critical role in antitumor immunity. TRAIL interacts with the death receptors, DR4 and DR5, and activates intracellular apoptotic pathway in cancer cells. This discovery has resulted in a rapid development of cancer therapeutic agents that can activate this apoptotic pathway. These therapeutic agents include recombinant human TRAIL (rhTRAIL) and its agonistic monoclonal antibody (MAb) against DR4 and DR5. Phase I trials have established the safety and tolerability of these TRAIL agonists in patients. Phase II trials are currently evaluating the therapeutic efficacy of TRAIL agonists as single agents or in combination with established cancer therapeutics. This review outlines the advances and the challenges in the development of these TRAIL agonists as effective clinical cancer therapeutics.
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Lung epithelial apoptosis in influenza virus pneumonia: The role of macrophage-expressed TNF-related apoptosis-inducing ligand
Article
Full-text available
Mononuclear phagocytes have been attributed a crucial role in the host defense toward influenza virus (IV), but their contribution to influenza-induced lung failure is incompletely understood. We demonstrate for the first time that lung-recruited "exudate" macrophages significantly contribute to alveolar epithelial cell (AEC) apoptosis by the release of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a murine model of influenza-induced pneumonia. Using CC-chemokine receptor 2-deficient (CCR2(-/-)) mice characterized by defective inflammatory macrophage recruitment, and blocking anti-CCR2 antibodies, we show that exudate macrophage accumulation in the lungs of influenza-infected mice is associated with pronounced AEC apoptosis and increased lung leakage and mortality. Among several proapoptotic mediators analyzed, TRAIL messenger RNA was found to be markedly up-regulated in alveolar exudate macrophages as compared with peripheral blood monocytes. Moreover, among the different alveolar-recruited leukocyte subsets, TRAIL protein was predominantly expressed on macrophages. Finally, abrogation of TRAIL signaling in exudate macrophages resulted in significantly reduced AEC apoptosis, attenuated lung leakage, and increased survival upon IV infection. Collectively, these findings demonstrate a key role for exudate macrophages in the induction of alveolar leakage and mortality in IV pneumonia. Epithelial cell apoptosis induced by TRAIL-expressing macrophages is identified as a major underlying mechanism.
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Role of the Chemokine Receptor CXCR2 in Bleomycin-Induced Pulmonary Inflammation and Fibrosis
Article
Full-text available
  • Nov 2008
  • AM J RESP CELL MOL
Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-induced pulmonary fibrosis. CXCL1/KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1,) and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-induced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.
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Interstitial Lung Diseases of Unknown Cause: Disorders Characterized by Chronic Inflammation of the Lower Respiratory Tract (First of Two Parts)
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  • Feb 1984
THE interstitial lung diseases are a heterogeneous group of disorders of the lower respiratory tract characterized by derangements of the alveolar walls and loss of functional alveolar capillary units.1 2 3 More than 100 agents are known to cause interstitial disease, but in two thirds of all cases, no cause can be identified.3 This group, commonly referred to as interstitial lung diseases of unknown cause, is responsible for more than 10,000 hospital admissions in the United States each year and has a prevalence of 5 to 10 cases per 100,000 population.3 The list of interstitial lung diseases of unknown cause includes 35 . . .
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Mechanism of neutrophil accumulation in the lungs of patients with idiopathic pulmonary fibrosis
Article
  • Aug 1981
Neutrophils are a characteristic feature of the alveolitis of idiopathic pulmonary fibrosis (IPF). a chronic disorder limited to lung. One mechanism by which neutrophils may be selectively attracted to lung and not other tissues is via the secretion of the neutrophil-specific chemotactic factor by alveolar macrophages. To evaluate the role of alveolar macrophages in modulating the migration of neutrophils to he lung in IPF, alveolar macrophages, obtained by bronchoalveolar lavage of patients with IPF, were evaluated for their ability to release a chemotactic factor for neutrophils. Unstimulated alveolar macrophages from normal individuals did not release the factor. In patients with IPF, there was a significant correlation between the proportions of neutrophils in lavage fluid and the release of a chemotactic factor for neutrophils by alveolar macrophages (p less than 0.001). The chemotactic factor released by IPF alveolar macrophages was of low molecular weight (400-600), at least partially lipid in nature, and preferentially attracted neutrophils compared with monocytes. Several lines of evidence suggested that immune complexes in the lung stimulated alveolar macrophages of patients with IPF to release the chemotactic factor. First, immune complexes stimulated normal macrophages to release the factor.Second, there was a significant correlation between the release of the chemotactic factor by IPF alveolar macrophages and the levels of immune complexes in bronchoalveolar lavage fluid. Third, bronchoalveolar lavage fluid containing immune complexes stimulated normal macrophages to release the factor. Fourth, IPF alveolar macrophages that released large amounts of the chemotactic factor had an apparent suppression of their immunoglobulin (Ig)G Fc receptor function, suggesting that immune complexes were bound to their surface. In contrast, the IgG Fc receptor function of IPF alveolar macrophages that released only small amounts of the factor was similar to that of normal macrophages. These studies suggest that neutrophils are attracted to the lung in patients with IPF by a potent chemotactic factor released by alveolar macrophages that have been stimulated, in vivo, via their IgG Fc receptor by immune complexes.
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