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Cigarette smoke-induced lung inflammation in COPD mediated via CCR1/JAK/STAT /NF-κB pathway

Cigarette smoke-induced lung inflammation in COPD mediated via CCR1/JAK/STAT /NF-κB pathway


Abstract

Inflammation is an important cause of chronic obstructive pulmonary disease (COPD) and its acute exacerbation. However, the critical role of C-C chemokine receptor (CCR)1 in progression of cigarette smoke-induced chronic inflammation remains unclear. We studied CCR1 expression using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction (RT-PCR) in COPD patients and controls. Cytokine levels in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, we investigated Janus kinase/signal transducers and activators of transcription (JAK/STAT)/nuclear factor-κB (NF-κB) signaling in cigarette smoke extract-induced or CCR1 deficiency/overexpressed mouse macrophage cell line MH-S by RT-PCR and western blot, and measured the cytokine levels in the supernatant with ELISA. We found that CCR1 expression was upregulated in COPD patients and there was a negative correlation between CCR1 mRNA levels and predicted % forced expiratory volume in 1 min. Inflammatory cytokine levels in the peripheral blood were higher in COPD patients than controls, and these were positively correlated with CCR1 levels. CCR1 was shown to play a critical role in regulating smoke-induced inflammation via JAK/STAT3/NF-κB signaling in vitro. CCR1 may play a critical role in airway inflammation in COPD. Additionally, understanding the molecular mechanism may help develop novel methods for the treatment of COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and concurrent progressive airflow limitation [1–3]. Patients may experience episodes of exacerbated respiratory symptoms, and the frequency of exacerbations requiring hospitalization increases, resulting in significant social and economic burden and one of the major causes of morbidity and mortality worldwide [4, 5]. The pathogenesis of COPD and exacerbations may be associated with inflammatory cells, including macrophages, neutrophils, and T lymphocytes [6, 7]. These cells are crucial in parenchymal destruction and development of airflow limitation in patients with COPD [8, 9].

Chemokines and their receptors regulate leukocyte adhesion and homing, and these receptors play a critical role in trafficking of leukocytes to sites of injury and inflammation [10]. In fact, the cell surface of T cells, natural killer cells, monocytes, macrophages, lymphocytes, and neutrophils express the C-C chemokine receptor (CCR)1 [11]. Previous studies have shown that elevated blood inflammation cells, chemokine levels, and CCR1 expression are associated with increased risk of exacerbations in patients with COPD [12–16]. However, the critical role of CCR1 in the progression of cigarette smoke-induced chronic inflammation remains unclear. We therefore hypothesize that CCR1 enhances airway inflammation via regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT)/nuclear factor-κB (NF-κB) signaling.

In this study, we aimed to assess CCR1 expression in peripheral blood and bronchial tissues of patients with COPD and participants who served as controls. Furthermore, we investigated chemokine levels in plasma and correlation with lung function and CCR1 expression. We also aimed to examine the inflammatory responses of MH-S cells that overexpressed or were deficient in CCR1 expression that were treated with cigarette smoke extract (CSE). https://www.aging-us.com/article/103180/text


When public refer to contemporary medicine, accuracy plays one of the most significant roles and human lives are literally dependent on it. Hence, any researches pertaining to medicine are necessary to meet the highest standards. The problem today is that any results of researches can be published online and used as a reference without being adequately verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and decided to create an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been established back in 2010. The major principle of this journal is based on Altmetric scores that are used as a quality indicator. That allows both readers and authors to validate publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a complete publications list with respective scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the necessary help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and written by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to understand the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Hereby, the paper about melanoma, was utilized for citations in various news articles 69 times. Moreover, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get helpful scientific facts. Oncotarget is proud to have the ability to share with online readers this highly appreciated and top-quality information, that is trustworthy and reliable.

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