Rekha D, Johnson P, Das S, Rajagopalan B, Sathya G, Sekhar L. Comparative Study on Soluble Urokinase-Type Plasminogen Activator Receptor (Supar) and C-Reactive Protein (Crp) Levels in Stable Chronic Obstructive Pulmonary Disease. Biomed Pharmacol J 2022;15(3).

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Manuscript received on :18-12-2021
Manuscript accepted on :30-07-2022
Published online on: 06-09-2022

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Plagiarism Check: Yes
Reviewed by: Dr. Sunil Jagtap
Second Review by: Dr. Sharad Kamble
Final Approval by: Dr. Jihan Seid Hussein

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Rekha D¹, Priscilla Johnson^2*, Subhasis Das¹, Rajagopalan B³, Sathya GR¹ and Lavanya Sekhar²

¹Department of Physiology; Pondicherry Institute of Medical Sciences, Puducherry-605014, India.

²Department of Physiology; Sri Ramachandra Medical College and Research Institute, SRIHER, Porur, Chennai- 600116, India.

³Department of Chest and TB; Sri Ramachandra Medical College and Research Institute, SRIHER, Porur, Chennai- 600116, India

Corresponding Author Email: priscillajohnson@sriramachandra.edu.in

DOI : https://dx.doi.org/10.13005/bpj/2464

Abstract

Background and objective: Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and irreversible airflow limitation. In COPD, the initial low-grade pulmonary inflammation slowly progress to systemic inflammation which is usually confirmed by non-specific inflammatory biomarker like C-reactive protein (CRP). However, the disease progress can be diagnosed at the early stage of pulmonary inflammation by using a novel biomarker, like Soluble urokinase-type plasminogen activator receptor (suPAR) released from the respiratory epithelium in COPD. The objective of this study was to compare the serum levels of suPAR and CRP in stable COPD and to assess the progress of low-grade pulmonary inflammation in COPD. Methods: Stable COPD [SCOPD] study participants (male-35; female-15) and healthy controls (male-38; female-12) were recruited for the study after obtaining informed consent. Based on post-bronchodilator FEV1% predicted values as specified by GOLD criteria, SCOPD study participants were graded into grades I-IV. Serum suPAR and CRP assays were done for all the study participants. Results: The level of suPAR among SCOPD grades I-IV (4.03±0.40 ng/ml; 5.16 ±0.26 ng/ml; 5.82±0.17ng/ml; 6.39±0.07ng/ml respectively) were high compared to healthy control (1.84±0.90ng/ml) and  was statistically significant. The level of CRP  among SCOPD grade I-IV (3.30±0.13 ng/ml; 3.60 ±0.09 ng/ml; 3.91±0.12ng/ml; 4.41±0.10 ng/ml respectively) were high compared to healthy control (1.63±0.77ng/ml) and was statistically significant.. Conclusion: Our study indicated that serum suPAR  and CRP may play an important role in the inflammatory process of COPD particularly in grades III and IV SCOPD. Hence, serum suPAR and CRP measurements may be useful for the evaluation and prognosis of stable COPD.

Keywords

Biomarker; COPD; Inflammation; Pulmonary; suPAR

Introduction

Chronic Obstructive Pulmonary Disease (COPD) occurs due to inflammatory lung response characterised by progressive airflow obstruction.^1,2  Lung parenchymal destruction with decrease in mucociliary clearance (MCC) and phagocytic activity of alveolar macrophages occurs leading to an increased risk of exacerbation.  This alteration in the lung defence mechanism and oxidative stress can lead to mortality among exposed due to COPD^3-7.

Conventionally, the diagnosis for SCOPD was by clinical symptoms and pulmonary function test (PFT).  However, there is a need for a better tool to monitor prognosis of COPD. In the ECLIPSE cohort studies for COPD, previous exacerbation, older age, increased WBC count and poor health status were associated with increased risk of future hospitalization. Various biomarkers like C-reactive protein (CRP) and fibrinogen  have been assessed to know the association of disease severity and mortality risk among COPD patients. Recent systematic review has showed that CRP was consistently elevated in COPD patients compared with control groups. However, these routine non-specific markers are not reliable for assessing disease mortality and prognosis.

Recent studies have shown that suPAR is a more stable biomarker for low-grade pulmonary inflammation. The cleavage of urokinase plasminogen activator receptor (uPAR) from the inflamed respiratory epithelium into suPAR, reflects the pathogenesis (both small airway fibrosis and emphysema) of COPD through complex molecular pathways and gene expression patterns.  Assessment of serum suPAR reflects lung function impairment during acute exacerbation and for monitoring treatment response..^5,8,9

Hence, this study was conducted to compare the serum levels of suPAR and CRP in stable COPD study participants in order to assess the progress of low-grade pulmonary inflammation in COPD.

AIM

To assess and compare the serum soluble urokinase-type plasminogen activator receptor (suPAR) and C-reactive protein (CRP) levels in stable COPD. 

Methodology

After obtaining IEC clearance Institutional Ethics Committee [IEC-NI/17/JUN/60/59], this cross- sectional study was carried out in a private medical college hospital in Puducherry, South India among stable COPD study participants. SCOPD study participants (n=50) with history of dyspnoea, chronic cough and sputum production for a period of 3 months for 2 consecutive years and apparently healthy controls (n=50) aged between 35-65 years inclusive of both sexes were included in the study based on the selection criteria after getting informed consent. Subjects with history of bronchial asthma, bronchiectasis, cystic fibrosis, collagen tissue disease, cirrhosis of liver and renal failure with conditions that could affect serum suPAR and CRP levels were excluded from the study. General information such as age, gender, occupation, literacy status, smoking status and socio-economic status were collected using a standard questionnaire. Study participants were subjected to spirometry and post-bronchodilator testing and were then grouped into grades I – IV as per Global Initiative for Obstructive Lung Disease (GOLD) criteria¹⁰. Blood samples were collected from the study participants and serum suPAR and CRP levels were measured using Abcam’s  Human ELISA (Enzyme- Linked Immunosorbent Assay) kit.¹¹

Statistical Analysis

Results were tabulated in EXCEL and data analysis was done by using SPSS software version 20.0. The difference between control group and different grades of SCOPD were analysed using ANOVA.

Result

The present cross-sectional study was conducted among 50 SCOPD study participants and 50 apparently healthy controls with age group 35 to 65 years. The distribution of study participants based on age, gender, occupation, literacy status, socio-economic and smoking status is shown in Table 1.

Table 1: Descriptive characteristics of the study population

Table 2 shows Mean ± SD for Pulmonary function parameters like Forced expiratory volume in the 1^st second (FEV1% predicted), Forced Vital Capacity (FVC), FEV1/FCV ratio, peak expiratory flow rate (PEFR) for control group and mean ± SD for post-bronchodilator parameters like FEV1% predicted, FVC, FEV1/FVC ratio and  for SCOPD participants.

Table 2: Pulmonary function test parameters of the study participants.

Table 3 represents Mean ± SD  values for serum suPAR and CRP level among different SCOPD grades and controls. It was observed that levels of suPAR and CRP among SCOPD were high compared to healthy control. In addition, Serum suPAR and CRP levels were high among GOLD IV and III compared to GOLD II and I ,which was statistically significant (p=0.000).

Table 3: Comparison of  Serum suPAR level and  CRP among different grades of SCOPD and control participants.

^* p<0.05- STATISTICALLY significant

Discussion

This cross-sectional study which involved SCOPD participants (grade I to IV) and healthy controls showed that the plasma suPAR level was higher among SCOPD grade III and IV compared to grade I and II. This indicates the  role of urokinase plasminogen activator system  in lung parenchymal destruction and small airway fibrosis. Similar finding has been reported by Can U et al., who observed that serum suPAR was high among grade III and IV than grade I,II and control groups ¹²

Moreover, the raised suPAR level in SCOPD participants in our study could be due to increased expression of suPAR in the small airway epithelia and pulmonary epithelial-mesenchymal transition process among SCOPD patients which lead to disease progression and it could also be due to  increased expression of urokinase plasminogen activator receptor in the small airway epithelia of  SCOPD patients which contributes for the airflow limitation due to activation of inflammatory immune response. Similar  finding is reported by a  study done by Wang et al.,and Godtfredsen et al., which shows suPAR level was higher among grade IV SCOPD when compared to grade I-III and normal subjects^13,14.   Besides, studies done by Prins HJ and AboEl-Magd GH have also shown that serum suPAR was high among SCOPD than normal individuals due to activation of pulmonary inflammation.^15,16

In this study, it was observed that CRP levels were also elevated in SCOPD study participants when compared to the controls.  Similar observation was reported in a study which  indicated CRP as a promising diagnostic marker among SCOPD.¹⁷ Study done by Al-Aarag et al.,and  and Zhang et al.,also found a significant difference between the  COPD and the control group in relation to the CRP level which was similar to our study results. ^18,19  

Systematic review done by few researchers confirmed that CRP levels increases in patients with stable COPD among different grades with decline in lung function.^20,21 Yende S et al., and Broekhuizen R et al.,  also observed that the CRP level was  high among SCOPD than normal individuals and the difference was statistically significant.^22,23 In a study done by Sever  ZK et al., it was  reported that serum CRP and suPAR levels were high among COPD patients which suggested that they have significant roles in systemic inflammation associated with worse prognosis and severity.²⁴ 

Similarly, meta-analysis has  shown that serum suPAR was high among grade IV compared to grade I and the level of suPAR correlated with diseases severity hence suPAR was suggested to be used clinically to monitor COPD patients on treatment and  their prognosis.²⁵ In addition suPAR is a very stable biomarker when compared to CRP, less affected by the exacerbation and directly related to disease severity which favours its high prognostic value for COPD.²⁶ 

Limitation of the Study

Drug intervention with novel anti-inflammatory therapy and follow up for lung function decline was not done to rule out ongoing pulmonary inflammation among stable COPD patients.

Conclusion

The study results support that suPAR and CRP can be used as surrogative biomarker to predict the inflammatory changes among COPD patients. suPAR seems to be independent, stable biomarker when compared to CRP, less affected by the exacerbation and is  better than CRP in discriminating adverse outcome and severity progression. Further, prospective studies need to be conducted to explore whether suPAR can be used as a novel biomarker in predicting the severity of SCOPD in the early stages of disease.    

Acknowledgment

I would like to thank all the participants who voluntarily participated in this study. I thank Mr.Manikandan for helping me in statistical analysis.

Conflict of Interest

There is no conflict of interest.

Funding Source

Science and Engineering Research Board (SERB).

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