Guanylyl cyclase activation reverses resistive breathing–induced lung injury and inflammation

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure–volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC–cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases

Changes in the expression of fibril-forming collagen types in non small cell lung cancer

Purpose: Research concerning the molecular mechanisms of non-small cell lung cancer (NSCLC) development may provide biological markers for novel diagnostic and therapeutic strategies. Invasion of the extracellular matrix (ECM) is a crucial hallmark in tumor metastasis.It has been shown that the expression of collagen changes in malignancies, especially that of collagen XI. This would affect the ability of cancer cells to invade the stroma and metastasize. The a1 chain of collagen XI is transcribed from COL11A1 gene by alternative splicing in at least four different transcripts (termed A, B, C and E). The corresponding protein isoforms differ in the proteolysis of the N-terminus and potentially, in the way that mediate invasion in the extracellular matrix. The purpose of the study was the development of new quantitative methodologies for the general (total) COL11A1 and the C transcript (RT-qPCR methods for A and E transcripts have already been developed by our group previously), the quantification of all COL11A1 transcripts in Non Small Cell Lung Cancer and the investigation for the first time of their potential association with histopathological prognostic factors in lung cancer.Methods: Surgical lung samples from 23 patients with NSCLC and 6 patients without cancer (control group) were taken from the tumor site in cancer patients and healthy normal lung site in the control group. Real-time quantitative RT-PCR was performed with special primers for collagen type ΧΙ(α1). Real-time RT-qPCR methodologies for different transcriptis with dual hybridization probes were developed on the Light Cycler 1.5 platform (Roche, Germany). All COL11A1 transcripts were measured in 27 cDNA lung tissue specimens in a blinded fashion (8 control and 19 non-small cell lung cancer tissues with known histopathological data). Statistical analysis was performed with the IBM SPSS program.Results: Quantitive RT-PCR revieled that Collagen type XI(α1) was significantly upregulated in NSCLC sampled compared to the control group (p=0.004). There was a significant increase in the mRNA expression levels for Collagen type XI(α1) in early NSCLC stage I (6.7-fold increase). During the follow-up period (1.5±0.5 years), patients who died or has disease relapse had a 8.5-fold increase in Collagen type XI(α1) levels, compared to 3.5-fold increase in patients without disease progression (P=0.009). All 19 NSCLC samples were positive for the general COL11A1 transcript (range 11.2-1198.0 copies/μg total RNA, while five out of eight control samples were negative: mean values were also statistically significantly different (p<0.001). In four tumor samples (21%), no specific COL11A1 transcript was detected. Transcript C was detected in only three tumor samples. Regarding transcripts A and E, 13 out of 19 tumor samples were positive for either one (68%) and 11 for both (58%). Conclusions: The results indicate that increased expression levels of Collagen type XI(α1) in NSCLC may correlate to prognosis. No other statistically significant association of the specific transcripts with histopathological data was observed most probably due to the limited number of samples. As the number of general COL11A1 transcripts/µg exceeds the sum of A+E+C transcripts in all samples, there is opportunity for discovery and identification of other transcripts as well. Further investigation in this biomarker may have the potential to provide a biomarker in selecting patients needing more aggressive treatment approaches.Εισαγωγή: Η έρευνα των μοριακών μηχανισμών στην ανάπτυξη του μη-μικροκυτταρικού καρκίνου πνεύμονα (ΜΜΚΠ) μπορεί να αποδώσει βιολογικούς δείκτες για νέες διαγνωστικές και θεραπευτικές στρατηγικές. Η διήθηση του εξωκυττάριου δικτύου (ΕΚΔ) είναι κρίσιμο στάδιο στην επέκταση και την μετάσταση του καρκίνου.Έχει δειχθεί ότι οι αλλαγές στην έκφραση των κολλαγόνων σε κακοήθειες, ειδικά του κολλαγόνου ΧΙ, επηρεάζοντας την ικανότητα του όγκου για διήθηση και μετάσταση. Η αλυσίδα α1 του κολλαγόνου ΧΙ ελέγχεται από το γονίδιο COL11A1, η μεταγραφή του οποίου οδηγεί σε τέσσερεις ισομορφές της αλυσίδας α1 (A,Β,C και Ε). Η αλυσίδες αυτές διαφέρουν στην πρωτεόλυση του Ν-αμινοτελικού άκρου, με τρόπο που ευνοείται η διήθηση και η μετάσταση. Σκοπός της μελέτης είναι η ανάπτυξη νέων ποσοτικών μεθοδολογιών ανάλυσης για το γενικό μετάγραφο του COL11A1 και την ισομορφή C, η ποσοτικοποίηση όλων των ισομορφών στον μη-μικροκυτταρικό καρκίνο πνεύμονα, κι η συσχέτιση για πρώτη φορά με ιστοπαθολογικούς προγνωστικούς παράγοντες στον καρκίνο του πνεύμονα. Μέθοδοι: Χειρουργικά δείγματα πνεύμονα από 23 ασθενείς με ΜΜΚΠ και 6 ασθενείς χωρίς καρκίνο, ελήφθησαν για την μελέτη της έκφρασης του κολλαγόνου ΧΙ(α1). Real-time RT-qPCR μεθοδολογίες με υβριδισμό διπλού probe αναπτύχθηκαν στην πλατφόρμα Light Cycler 1.5 (Roche, Germany). Τα μετάγραφα των ισομορφών του COL11A1 μετρήθηκαν σε cDNA από 27 δείγματα ιστού πνεύμονα (8 δείγματα ελέγχου και 19 δείγματα ιστού ΜΜΚΠ με γνωστά ιστοπαθολογικά δεδομένα). Η στατιστική ανάλυση έγινε με το πρόγραμμα IBM SPSS.Αποτελέσματα: Η ποσοτική αντίδραση RT-PCR έδειξε ότι το κολλαγόνο τύπου XI(α1) ήταν σημαντικά αυξημένο στα δείγματα του ΜΜΚΠ σε σύγκριση με την ομάδα ελέγχου (P=0.004). Υπήρξε αύξηση της έκφρασης των επιπέδων mRNA του κολλαγόνου τύπου XI(α1) στο πρώιμο στάδιο Ι του ΜΜΚΠ. Κατά την περίοδο παρακολούθησης (1.5±0.5 έτη), οι ασθενείς που απεβίωσαν ή είχαν υποτροπή είχαν 8,5 φορές αύξηση των επιπέδων κολλαγόνου τύπου XI(α1) σε σύγκριση με 3,5 φορές αύξηση όσων είχαν επιζήσει χωρίς υποτροπή (P=0.009). Όλα τα 19 δείγματα του ΜΜΚΠ, που αναλύθηκαν για τις ισομορφές, ήταν θετικά για το γενικό μετάγραφο του COL11A1 (εύρος 11.2-1198.0 copies/μg ολικού RNΑ) ενώ 5 πό τα 8 δείγματα ελέγχου ήταν εντελώς αρνητικά. Η διαφορά των μέσων τιμών επίσης ήταν στατιστικά σημαντική (p<0.001). Σε 4 δείγματα ΜΜΚΠ (21%) δεν βρέθηκε μετάγραφο ισομορφής. Το μετάγραφο της ισομορφής C ανιχνεύθηκε μόνο σε 3 δείγματα όγκου. Όσον αναφορά τις ισομορφές A και E, 13 από τα 19 δείγματα ήταν θετικά για τουλάχιστον ένα από τα δύο (68%) και 11 και τα δύο (58%).Συμπεράσματα: Τα αποτελέσματα καταδεικνύουν ότι η αυξημένη έκφραση του κολλαγόνου τύπου XI(α1) στον ΜΜΚΠ σχετίζεται με την πρόγνωση. Δεν προέκυψαν στατιστικά σημαντικές συσχετίσεις συγκεκριμένων μετάγραφων ισομορφών με ιστοπαθολογικά δεδομένα που παρατηρήθηκαν, λόγω του μικρού αριθμού δειγμάτων. Δεδομένου ότι ο αριθμός των μετάγραφων ανά μg του COL11A1 υπερβαίνει τον συνολικό αριθμό των μετάγραφων των ισομορφών A+E+C σε όλα τα δείγματα, υπάρχει η προοπτική ανακάλυψης και ταυτοποίησης επιπλέον ισομορφών. Ο συγκεκριμένος δείκτης ενδεχομένως να έχει αξία στην επιλογή των ασθενών που θα ωφεληθούν από παραπέρα συμπληρωματική χημειοθεραπεία

Αλλαγές στην έκφραση τύπων κολλαγόνου σχηματίζουν ινίδια στον μη-μικροκυτταρικό καρκίνο του πνεύμονα

Εισαγωγή: Η έρευνα των μοριακών μηχανισμών στην ανάπτυξη του μη-μικροκυτταρικού καρκίνου πνεύμονα (ΜΜΚΠ) μπορεί να αποδώσει βιολογικούς δείκτες για νέες διαγνωστικές και θεραπευτικές στρατηγικές. Η διήθηση του εξωκυττάριου δικτύου (ΕΚΔ) είναι κρίσιμο στάδιο στην επέκταση και την μετάσταση του καρκίνου.Έχει δειχθεί ότι οι αλλαγές στην έκφραση των κολλαγόνων σε κακοήθειες, ειδικά του κολλαγόνου ΧΙ, επηρεάζοντας την ικανότητα του όγκου για διήθηση και μετάσταση. Η αλυσίδα α1 του κολλαγόνου ΧΙ ελέγχεται από το γονίδιο COL11A1, η μεταγραφή του οποίου οδηγεί σε τέσσερεις ισομορφές της αλυσίδας α1 (A,Β,C και Ε). Η αλυσίδες αυτές διαφέρουν στην πρωτεόλυση του Ν-αμινοτελικού άκρου, με τρόπο που ευνοείται η διήθηση και η μετάσταση. Σκοπός της μελέτης είναι η ανάπτυξη νέων ποσοτικών μεθοδολογιών ανάλυσης για το γενικό μετάγραφο του COL11A1 και την ισομορφή C, η ποσοτικοποίηση όλων των ισομορφών στον μη-μικροκυτταρικό καρκίνο πνεύμονα, κι η συσχέτιση για πρώτη φορά με ιστοπαθολογικούς προγνωστικούς παράγοντες στον καρκίνο του πνεύμονα. Μέθοδοι: Χειρουργικά δείγματα πνεύμονα από 23 ασθενείς με ΜΜΚΠ και 6 ασθενείς χωρίς καρκίνο, ελήφθησαν για την μελέτη της έκφρασης του κολλαγόνου ΧΙ(α1). Real-time RT-qPCR μεθοδολογίες με υβριδισμό διπλού probe αναπτύχθηκαν στην πλατφόρμα Light Cycler 1.5 (Roche, Germany). Τα μετάγραφα των ισομορφών του COL11A1 μετρήθηκαν σε cDNA από 27 δείγματα ιστού πνεύμονα (8 δείγματα ελέγχου και 19 δείγματα ιστού ΜΜΚΠ με γνωστά ιστοπαθολογικά δεδομένα). Η στατιστική ανάλυση έγινε με το πρόγραμμα IBM SPSS. Αποτελέσματα: Η ποσοτική αντίδραση RT-PCR έδειξε ότι το κολλαγόνο τύπου XI(α1) ήταν σημαντικά αυξημένο στα δείγματα του ΜΜΚΠ σε σύγκριση με την ομάδα ελέγχου (P=0.004). Υπήρξε αύξηση της έκφρασης των επιπέδων mRNA του κολλαγόνου τύπου XI(α1) στο πρώιμο στάδιο Ι του ΜΜΚΠ. Κατά την περίοδο παρακολούθησης (1.5±0.5 έτη), οι ασθενείς που απεβίωσαν ή είχαν υποτροπή είχαν 8,5 φορές αύξηση των επιπέδων κολλαγόνου τύπου XI(α1) σε σύγκριση με 3,5 φορές αύξηση όσων είχαν επιζήσει χωρίς υποτροπή (P=0.009). Όλα τα 19 δείγματα του ΜΜΚΠ, που αναλύθηκαν για τις ισομορφές, ήταν θετικά για το γενικό μετάγραφο του COL11A1 (εύρος 11.2-1198.0 copies/μg ολικού RNΑ) ενώ 5 πό τα 8 δείγματα ελέγχου ήταν εντελώς αρνητικά. Η διαφορά των μέσων τιμών επίσης ήταν στατιστικά σημαντική (p&lt;0.001). Σε 4 δείγματα ΜΜΚΠ (21%) δεν βρέθηκε μετάγραφο ισομορφής. Το μετάγραφο της ισομορφής C ανιχνεύθηκε μόνο σε 3 δείγματα όγκου. Όσον αναφορά τις ισομορφές A και E, 13 από τα 19 δείγματα ήταν θετικά για τουλάχιστον ένα από τα δύο (68%) και 11 και τα δύο (58%). Συμπεράσματα: Τα αποτελέσματα καταδεικνύουν ότι η αυξημένη έκφραση του κολλαγόνου τύπου XI(α1) στον ΜΜΚΠ σχετίζεται με την πρόγνωση. Δεν προέκυψαν στατιστικά σημαντικές συσχετίσεις συγκεκριμένων μετάγραφων ισομορφών με ιστοπαθολογικά δεδομένα που παρατηρήθηκαν, λόγω του μικρού αριθμού δειγμάτων. Δεδομένου ότι ο αριθμός των μετάγραφων ανά μg του COL11A1 υπερβαίνει τον συνολικό αριθμό των μετάγραφων των ισομορφών A+E+C σε όλα τα δείγματα, υπάρχει η προοπτική ανακάλυψης και ταυτοποίησης επιπλέον ισομορφών. Ο συγκεκριμένος δείκτης ενδεχομένως να έχει αξία στην επιλογή των ασθενών που θα ωφεληθούν από παραπέρα συμπληρωματική χημειοθεραπεία.Purpose: Research concerning the molecular mechanisms of non-small cell lung cancer (NSCLC) development may provide biological markers for novel diagnostic and therapeutic strategies. Invasion of the extracellular matrix (ECM) is a crucial hallmark in tumor metastasis.It has been shown that the expression of collagen changes in malignancies, especially that of collagen XI. This would affect the ability of cancer cells to invade the stroma and metastasize. The a1 chain of collagen XI is transcribed from COL11A1 gene by alternative splicing in at least four different transcripts (termed A, B, C and E). The corresponding protein isoforms differ in the proteolysis of the N-terminus and potentially, in the way that mediate invasion in the extracellular matrix. The purpose of the study was the development of new quantitative methodologies for the general (total) COL11A1 and the C transcript (RT-qPCR methods for A and E transcripts have already been developed by our group previously), the quantification of all COL11A1 transcripts in Non Small Cell Lung Cancer and the investigation for the first time of their potential association with histopathological prognostic factors in lung cancer. Methods: Surgical lung samples from 23 patients with NSCLC and 6 patients without cancer (control group) were taken from the tumor site in cancer patients and healthy normal lung site in the control group. Real-time quantitative RT-PCR was performed with special primers for collagen type ΧΙ(α1). Real-time RT-qPCR methodologies for different transcriptis with dual hybridization probes were developed on the Light Cycler 1.5 platform (Roche, Germany). All COL11A1 transcripts were measured in 27 cDNA lung tissue specimens in a blinded fashion (8 control and 19 non-small cell lung cancer tissues with known histopathological data). Statistical analysis was performed with the IBM SPSS program. Results: Quantitive RT-PCR revieled that Collagen type XI(α1) was significantly upregulated in NSCLC sampled compared to the control group (p=0.004). There was a significant increase in the mRNA expression levels for Collagen type XI(α1) in early NSCLC stage I (6.7-fold increase). During the follow-up period (1.5±0.5 years), patients who died or has disease relapse had a 8.5-fold increase in Collagen type XI(α1) levels, compared to 3.5-fold increase in patients without disease progression (P=0.009). All 19 NSCLC samples were positive for the general COL11A1 transcript (range 11.2-1198.0 copies/μg total RNA, while five out of eight control samples were negative: mean values were also statistically significantly different (p&lt;0.001). In four tumor samples (21%), no specific COL11A1 transcript was detected. Transcript C was detected in only three tumor samples. Regarding transcripts A and E, 13 out of 19 tumor samples were positive for either one (68%) and 11 for both (58%). Conclusions: The results indicate that increased expression levels of Collagen type XI(α1) in NSCLC may correlate to prognosis. No other statistically significant association of the specific transcripts with histopathological data was observed most probably due to the limited number of samples. As the number of general COL11A1 transcripts/µg exceeds the sum of A+E+C transcripts in all samples, there is opportunity for discovery and identification of other transcripts as well. Further investigation in this biomarker may have the potential to provide a biomarker in selecting patients needing more aggressive treatment approaches

Acute exacerbation of COPD: is it the “stroke of the lungs”?

Chronic obstructive pulmonary disease (COPD) is one of the top five major causes of morbidity and mortality worldwide. Despite worldwide health care efforts, costs, and medical research, COPD figures demonstrate a continuously increasing tendency in mortality. This is contrary to other top causes of death, such as neoplasm, accidents, and cardiovascular disease. A major factor affecting COPD-related mortality is the acute exacerbation of COPD (AECOPD). Exacerbations and comorbidities contribute to the overall severity in individual patients. Despite the underestimation by the physicians and the patients themselves, AECOPD is a really devastating event during the course of the disease, similar to acute myocardial infarction in patients suffering from coronary heart disease. In this review, we focus on the evidence that supports the claim that AECOPD is the “stroke of the lungs”. AECOPD can be viewed as: a Semicolon or disease’s full-stop period, Triggering a catastrophic cascade, usually a Relapsing and Overwhelming event, acting as a Killer, needing Emergent treatment

Phenotyping and Endotyping Asthma Based on Biomarkers

Asthma is a chronic inflammatory airways disorder mainly characterized by heterogeneity. A phenotype is defined as a group of patients that present similar clinically observable characteristics, without establishing a direct etiologic relationship with a distinct pathophysiologic mechanism. An endotype, on the other hand, describes a subgroup that shares the same pathophysiologic processes that lead to the development, the progression and the presentation of a disease. A biomarker has been defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. Several inflammatory phenotypes have been identified by the use of biomarkers. Most of them are based on the predominant type of cells in different biological fluids with sputum to be remained the most representative one. Eosinophilia represents the major characteristic of what we called classic atopic asthma. This particular phenotype usually responds well to corticosteroids, except for a small subgroup of severe asthma where even in the presence of eosinophils the ICS seem to have a less responsive role. Neutrophilic phenotype driven by the presence of neutrophils shows inadequate response to corticosteroid treatment, even in mild asthma. The major approach in order to define an endotype is driven by three main parameters. The statistical clustering approach, the use of advanced statistical mathematics to create distinct patient clusters, the specific targeted immune therapies and finally the application of omics&apos; approach. Both phenotypes and endotypes are trying to clarify mechanisms and processes that driven the complexity of asthma. Both concepts could identify approaches which could establish new targeted to specific biomarkers treatment therapies/strategies

Key molecular mechanisms in lung cancer invasion and metastasis: A comprehensive review

Lung cancer remains one of the most common and malignant cancers worldwide. It is most often diagnosed at late stages, when it has already presented local invasion and distal metastases. The basic stages of invasion and metastasis involve the detachment of tumor cells from the extracellular matrix, invasion of surrounding tissues and basal lamina, intravasation into the blood stream, survival and transport through the blood stream, migration, arrest and extravasation at a distal site and formation of a metastatic lesion. These steps require fundamental mechanisms such as angiogenesis, degradation of matrix barriers, disruption of cell-cell and cell-matrix adhesion and inducement of cellular motility. Genes that regulate functions like unlimited growth potential, survival, genomic instability, angiogenesis, epithelial to mesenchymal transition and apoptosis evasion, are involved in giving lung cancer tumors invasive and metastatic competence. Improving of understanding of the underlying molecular and cellular mechanisms remains an urgent and essential issue, in order to develop new more effective strategies in preventing and treating lung cancer. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Managing comorbidities in COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities. COPD exacerbations and comorbidities contribute to the overall severity in individual patients. Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age. Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations. However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide. This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale. Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases. All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases. In this review, we focus on the major comorbidities that affect COPD patients. We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs. We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity

Managing comorbidities in COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Age and smoking are common risk factors for COPD and other illnesses, often leading COPD patients to demonstrate multiple coexisting comorbidities. COPD exacerbations and comorbidities contribute to the overall severity in individual patients. Clinical trials investigating the treatment of COPD routinely exclude patients with multiple comorbidities or advanced age. Clinical practice guidelines for a specific disease do not usually address comorbidities in their recommendations. However, the management and the medical intervention in COPD patients with comorbidities need a holistic approach that is not clearly established worldwide. This holistic approach should include the specific burden of each comorbidity in the COPD severity classification scale. Further, the pharmacological and nonpharmacological management should also include optimal interventions and risk factor modifications simultaneously for all diseases. All health care specialists in COPD management need to work together with professionals specialized in the management of the other major chronic diseases in order to provide a multidisciplinary approach to COPD patients with multiple diseases. In this review, we focus on the major comorbidities that affect COPD patients. We present an overview of the problems faced, the reasons and risk factors for the most commonly encountered comorbidities, and the burden on health care costs. We also provide a rationale for approaching the therapeutic options of the COPD patient afflicted by comorbidity

Incorporating Biomarkers in COPD Management: The Research Keeps Going

Globally, chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality, having a significant socioeconomic effect. Several molecular mechanisms have been related to COPD including chronic inflammation, telomere shortening, and epigenetic modifications. Nowadays, there is an increasing need for novel therapeutic approaches for the management of COPD. These treatment strategies should be based on finding the source of acute exacerbation of COPD episodes and estimating the patient&rsquo;s own risk. The use of biomarkers and the measurement of their levels in conjunction with COPD exacerbation risk and disease prognosis is considered an encouraging approach. Many types of COPD biomarkers have been identified which include blood protein biomarkers, cellular biomarkers, and protease enzymes. They have been isolated from different sources including peripheral blood, sputum, bronchoalveolar fluid, exhaled air, and genetic material. However, there is still not an exclusive biomarker that is used for the evaluation of COPD but rather a combination of them, and this is attributed to disease complexity. In this review, we summarize the clinical significance of COPD-related biomarkers, their association with disease outcomes, and COPD patients&rsquo; management. Finally, we depict the various samples that are used for identifying and measuring these biomarkers