This study aimed to validate automatic intravascular optical coherence tomography (IVOCT) analysis for the evaluation of neointimal coverage in response to stent implantation.
Fourteen stented ...segments in common iliac arteries, acquired from a total of seven adult male New Zealand White rabbits, were interrogated in vivo by IVOCT. Durable polymer everolimus-eluting stents (EES; Xience V, Abbott Vascular, Santa Clara, CA, USA) were used exclusively. Comparison with histology was made in a total of 63 pairs of images, where neointimal thickness over corresponding individual stent struts was assessed. A high correlation coefficient (R = 0.85, P < 0.001) was obtained by comparing automatic IVOCT analysis with histology. Moreover, Bland-Altman statistics showed good limits of agreement (LOAs) of ±45 µm, with an average difference of -10 µm. In addition, manual IVOCT assessment presented very similar results when compared with histology (R = 0.83, P < 0.001 and LOA = ±48 µm with an average difference of -8 µm). Therefore, a very high correlation value was found, comparing manual to automatic IVOCT measurements (R = 0.95, P < 0.001) together with good LOAs (±27 µm) and an average difference of -2 µm.
The results of the study suggest that automatic IVOCT analysis is a reliable and accurate tool able to speed up current IVOCT analysis procedures. This would potentially allow for a better integration of IVOCT in clinical practice and clinical studies assessing vascular response to stent implantation in a large series of patients.
Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible ...for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-α in myeloid cells in horse with recurrent airway obstruction.
In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-α), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-α mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-α mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction.
Taken together, our results suggest an important role for Hif1-α in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.
Zinc finger protein regulator of apoptosis and cell cycle arrest (Zac1) is a transcription factor able to induce apoptosis or cell cycle arrest through independent pathways. In spite of the important ...potential functions attributed to Zac1, little is known of its physiological regulation and biological function. We discovered that variant Zac1b was expressed in murine embryonic fibroblasts (MEFs) treated with polyriboinosinic polyribocytidylic acid poly(I:C), a synthetic double-stranded RNA. This regulation occurred mainly through Toll-Like Receptor 3 (TLR3)- and Interferon Regulatory Factor 3 (IRF3)-dependent pathways. As TLR3 and IRF3 are central activators of antiviral immunity, we hypothesized that Zac1 may be implicated in antiviral responses. In line with this notion, we observed that Zac1b was expressed in MEFs infected with Encephalomyocarditis virus (EMCV). We also observed that Zac1-deficient MEFs were less sensitive to EMCV-induced cell death than wild-type MEFs. However, Zac1 gene inactivation had no effect on the survival of mice infected with EMCV. In conclusion, this study describes for the first time a transcriptional regulation of Zac1b, induced by synthetic dsRNA and RNA viruses, the functional significance of which remains to be further investigated.
Very few transcription factors have been identified that are required by antigen-presenting cells (APCs) to induce T helper type 2 (Th2) responses. Because lung CD11b super(+) conventional dendritic ...cells (CD11b super(+) cDCs) are responsible for priming Th2 responses in house-dust mite (HDM)-induced airway allergy, we used them as a model to identify transcriptional events regulating the pro-Th2 activity of cDCs. Transcriptomic profiling of lung CD11b super(+) cDCs exposed to HDM in vivo revealed first that HDM triggers an antiviral defence-like response, and second that the majority of HDM-induced transcriptional changes depend on the transcription factor Interferon Response Factor-3 (Irf3). Validating the functional relevance of these observations, Irf3-deficient CD11b super(+) cDCs displayed reduced pro-allergic activity. Indeed, Irf3-deficient CD11b super(+) cDCs induced less Th2, more regulatory T cell, and similar Th1 differentiation in naive CD4 super(+) T cells compared to their wild-type counterparts. The altered APC activity of Irf3 CD11b super(+) cDCs was associated with reduced expression of CD86 and was phenocopied by blocking CD86 activity in wild-type CD11b super(+) cDCs. Altogether, these results establish Irf3, known mostly for its role in antiviral responses, as a transcription factor involved in the induction of Th2 responses through the promotion of pro-Th2 costimulation in CD11b super(+) DCs. House dust mite triggers an Irf3-dependent antiviral-like transcriptional program in lung resident type 2 conventional dendritic cells. This program promotes Th2 responses by increasing CD86 gene expression and hence CD86 costimulation. .
It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ T cells in human papillomavirus (HPV)-associated uterine ...cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5+ γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6+ γδlowCCR2+CCR6-) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.
Interferons (IFNs) are a group of cytokines with a well-established antiviral function. They can be induced by viral infection, are secreted and bind to specific receptors on the same or neighbouring ...cells to activate the expression of hundreds of IFN stimulated genes (ISGs) with antiviral function. Type I IFN has been known for more than half a century. However, more recently, type III IFN (IFNλ, IL-28/29) was shown to play a similar role and to be particularly important at epithelial surfaces. Here we show that airway epithelia, the primary target of influenza A virus, produce both IFN I and III upon infection, and that induction of both depends on the RIG-I/MAVS pathway. While IRF3 is generally regarded as the transcription factor required for initiation of IFN transcription and the so-called "priming loop", we find that IRF3 deficiency has little impact on IFN expression. In contrast, lack of IRF7 reduced IFN production significantly, and only IRF3-/-IRF7-/- double deficiency completely abolished it. The transcriptional response to influenza infection was largely dependent on IFNs, as it was reduced to a few upregulated genes in epithelia lacking receptors for both type I and III IFN (IFNAR1-/-IL-28Rα-/-). Wild-type epithelia and epithelia deficient in either the type I IFN receptor or the type III IFN receptor exhibit similar transcriptional profiles in response to virus, indicating that none of the induced genes depends selectively on only one IFN system. In chimeric mice, the lack of both IFN I and III signalling in the stromal compartment alone significantly increased the susceptibility to influenza infection. In conclusion, virus infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two completely overlapping and redundant amplification loops to upregulate ISGs and protect from influenza infection.
Conventional dendritic cells (DCs) are considered to be the prime initiators of airway allergy. Yet, it remains unclear whether specific DC subsets are preferentially involved in allergic airway ...sensitization. Here, we systematically assessed the respective pro-allergic potential of individually sorted lung DC subsets isolated from house dust mite antigen (HDM)-treated donor mice, following transfer to na#239;ve recipients. Transfer of lung CD11c.sup.+ CD11b.sup.+ DCs, but not CD11c.sup.+ CD11b.sup.- CD103.sup.+ DCs, was sufficient to prime airway allergy. The CD11c.sup.+ CD11b.sup.+ DC subpopulation was composed of CD11c.sup.+ CD11b.sup.+ Ly6C.sup.+ inflammatory monocyte-derived cells, whose numbers increase in the lungs following HDM exposure, and of CD11c.sup.+ CD11b.sup.+ Ly6C.sup.- DCs, which remain stable. Counterintuitively, only CD11c.sup.+ CD11b.sup.+ Ly6C.sup.- DCs, and not CD11c.sup.+ CD11b.sup.+ Ly6C.sup.+ DCs, were able to convey antigen to the lymph nodes and induce adaptive T cell responses and subsequent airway allergy. Our results thus support that lung resident non-inflammatory CD11c.sup.+ CD11b.sup.+ Ly6C.sup.- DCs are the essential inducers of allergic airway sensitization to the common aeroallergen HDM in mice.
Background Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes ...responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-alpha in myeloid cells in horse with recurrent airway obstruction. Results In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-alpha mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-alpha mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. Conclusion Taken together, our results suggest an important role for Hif1-alpha in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO. Keywords: Hypoxia inductible transcription factor-1, Recurrent airway obstruction, Inflammation, Lung, Horse
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