Elevated Serum Matrix Metalloprotease (MMP-2) as a Candidate Biomarker for Stable COPD

Durga Mahor; Vandana Kumari; Kapil Vashisht; Ruma Galgalekar; Ravindra M. Samarth; Pradyumna K. Mishra; Nalok Banerjee; Rajnikant Dixit; Rohit Saluja; Sajal De; Kailash C. Pandey

Disclosures

BMC Pulm Med. 2020;20(302) 

In This Article

Discussion

COPD is the most common respiratory diseases and is characterized by various degradative processes, remodelling of the extracellular matrix (ECM) and oxidative damage in the lung environment. It is imperative to distinctly identify robust biomarkers for COPD, as many of the symptoms of COPD often overlap with other respiratory diseases such as Asthma. In thi study, we investigated various serum protease, which can be exploited as candidate biomarkers for COPD. Notably, serum NE in COPD have been implicated in multiple studies- altered ratio of serum NE (protease) and α-1 antitrypsin (A1AT) (antiprotease) have been shown to be directly correlated with the disease severity;[7] in vivo NE activity has been reported as a marker for cross-sectional COPD disease severity.[25] Although serum NE has consistently been argued as a preliminary biomarker of COPD, our study reports elevated serum NE in both the respiratory illnesses (COPD and Asthma). Therefore, questioning the distinctiveness of serum NE as a biomarker for COPD. Suppression of inflammatory responses by DPP-IV has been previously reported in tumor biology by inactivating the neuropeptides, peptide hormones and chemokines. The quantitative analysis of DPP-IV from our study also corroborated the decrease in serum DPP-IV concentrations as an indicator of COPD. Due to the versatile inflammatory responses, resulting in altered DPP-IV activity, its specific role in COPD as a biomarker would be challenging to validate.

Caspase-7 has been termed as an executioner caspase with implications in cell death and proteolysis. It has also been previously reported to be upregulated in case of acute brain tissue injury in rats, suggesting its role in neuronal cell death.[26] It is known that caspase-7 in association with caspase-12 has been linked to the endoplasmic reticulum pathway of apoptosis which is induced via stress, and further activates the effector caspase-3.[6] The elevated caspase-7 (executioner caspase) could be responsible for the induction of inflammatory responses and cell death via apoptosis in COPD. An increased MMP-2 expression in the lung periphery has been reported to be associated with worsened lung function and increased emphysema, thus it is important for lung tissue remodelling and inflammation in COPD.[27] Corroborating the elevated MMP-2 in COPD, we report a significant increase in MMP-2 expression in COPD patients as compared to controls. The absence of lung tissue remodelling processes in Asthma as compared to COPD, also aligns well with our observation for nonsignificant difference in serum MMP-2 in controls and Asthma patients.

The mass spectrometric analysis of COPD proteome also identified positive fold-change in MMP-2 expression. We speculate that the difference in serum MMP-2 in COPD vs Asthma can be exploited as a differentiating biomarker between Asthma and COPD, along with other respiratory diseases in a larger cohort. The increased ROS in COPD patients is an indication of the elevated protease activities that results in upregulation of the cellular oxidative stress. Moreover, the increased ROS could also be correlated with the altered ionic balance and release of inflammatory cytokines which aid in the severity of the disease.

From the present study, following inferences have been made- 1) Serum NE cannot be used as distinctive biomarker of COPD, as we observed significantly higher serum NE in Asthma also; 2) decrease in DPP-IV could be due to suppression of inflammatory responses and hence does not specifically represent COPD signatures; 3) caspase-7, an executioner caspase which would have been recruited from multiple inflammatory signals, not specifically from COPD; 4) elevated ROS could also be a representation of higher protease activities and hence cannot be sourced alone from COPD and 5) increased MMP-2 expression, validated by ELISA as well as by mass spectrometric analysis, correlates well with emphysema in COPD, as well as in distinguishing Asthma from COPD.

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