Environmental Pollutants in COPD and Lung Cancer

Mitochondrial Dysfunction and Immune Checkpoints in Chronic Obstructive Pulmonary Disease (COPD) and Lung Cancer: the Role of Environmental Pollutants

Epidemiological studies describe a statistically significant correlation between hospitalization rate and exposure to environmental pollutants such as atmospheric particulates (PM10 and PM2.5) and polycyclic aromatic hydrocarbons (PAH). Indeed, they induced the release of inflammation mediators and oxidative stress, involved in remodeling and destruction of the alveolar parenchyma, in turn associated with the respiratory disease onset and progression such as asthma, COPD, pulmonary fibrosis and lung cancer. Interestingly, oxidative stress associated with environmental pollutants could also induce DNA damage by affecting the stability of G-quadruplex (G4) sequences. Given the role of G4 in physiological and pathological processes and their presence in mitochondrial DNA, telomeres and proto-oncogene promoters, it is interesting to investigate the potential involvement in cellular mechanisms of response to oxidative stress associated with pollutants. Moreover, it is known that pollutant-induced oxidative stress has the ability to alter mitochondrial integrity, leading to mitochondrial dysfunction. The mitochondria involvement in the innate and adaptive immune response regulation corroborates the role of pollutants in respiratory diseases pathogenesis. Indeed, mitochondrial function and integrity are critical for both the effector and memory stages of differentiation of T cells which play a primary role in respiratory diseases. In this context, the PD-1/PD-L1 immune check-points are essential in promoting the immune system homeostasis. Currently, although the role of environmental pollutants, mitochondrial dysfunction and the PD-1/PD-L1 axis in the pathogenesis of many respiratory diseases is recognized, it is useful to further clarify the underlying molecular interconnections and the mechanisms by which pollutants could affect mitochondrial integrity and immune checkpoints.

Study Overview

• Status: Recruiting
• Conditions: COPD and Lung Cancer
• Intervention / Treatment: Other: This is a cross-sectional, non pharmacological study

Detailed Description

Epidemiological studies describe a statistically significant correlation between hospitalization rate and exposure to environmental pollutants such as atmospheric particulates (PM10 and PM2.5). The harmfulness to human health depends on both the chemical composition and the particle size. Chronic exposure to particulate matter contributes to the risk of developing respiratory and cardiovascular diseases as well as may increase the risk of lung cancer. In fact, particulate matter is universally recognized as a Class 1 carcinogen. The fine particulates are harmful for human health by the ability to carry other pollutants such as polycyclic aromatic hydrocarbons (PAHs) to the lungs. Notably, the PAHs cause lung damage due to their ability to induce the release of inflammatory mediators and oxidative stress. These events result in remodeling and destruction of the alveolar parenchyma, both involved in respiratory disease onset and progression such as asthma, COPD, pulmonary fibrosis, and lung cancer. Therefore, the involvement of environmental pollutants in the predisposition and exacerbation of lung diseases, in the development of respiratory infections and in the process of carcinogenesis is evident. Moreover, in addition, oxidative stress associated with environmental pollutants could induce DNA damage. Recently, unconventional DNA structures have been identified, recognized as G-quadruplex (G4), which are particularly susceptible to oxidative stress. In fact, it is known that guanine-rich DNA sequences are more reactive with hydroxyl radicals than guanine residues scattered throughout the genome, and that oxidative damage (8-oxo-dg) formation at the G4 level reduces its thermal stability. Given the role of G4 in physiological and pathological processes and their presence in mitochondrial DNA, telomeres and proto-promoters oncogenes, it is interesting to investigate the potential involvement in cellular mechanisms of response to oxidative stress associated with pollutants. It is known that pollutant-induced oxidative stress has the ability to alter mitochondrial integrity, leading to mitochondrial dysfunction. Recent evidence points to innate immunity, apoptosis, and metabolism being largely regulated by mitochondrial activities. In turn, normal mitochondrial activity can be affected by inflammatory processes, infections, tobacco smoking and "environmental insults" and could respond to such stimuli through structural alterations and protein expression resulting in dysfunction. The mitochondria involvement in the innate and adaptive immune response regulation corroborates the role of pollutants in respiratory diseases pathogenesis. Indeed, mitochondrial function and integrity are critical for both the effector and memory stages of differentiation of T cells which play a primary role in respiratory diseases. In this context, the PD-1/PD-L1 immune check-points are essential in promoting the immune system homeostasis. Indeed, they take part in self-tolerance and consist of a series of ligand-receptor interactions involved in coordinating an effective immune response while limiting collateral damage to organs and tissues. The contribution of our research group in the study of the pathway PD-1/PD-L1 in the context of respiratory diseases was relevant, observing that this pathway is not only altered in lung cancer but also in chronic lung diseases such as COPD. Currently, although the role of environmental pollutants, mitochondrial dysfunction and the PD-1/PD-L1 axis in the pathogenesis of many respiratory diseases is recognized, it is useful to further clarify the underlying molecular interconnections and the mechanisms by which pollutants could affect mitochondrial integrity and immune checkpoints.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Bruno D'Agostino, MD, PhD; Phone Number: +393472601620; Email: bruno.dagostino@unicampania.it

Study Locations

• Italy
  • Napoli, Italy, 80131
    • Recruiting
    • Cardarelli Hospital
    • Contact: Giuseppe Failla, MD; Phone Number: +390817473391; Email: giuseppe.failla@aocardarelli.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients belong to UOC Interventional Pulmonology- Hospital Cardarelli and subjected to bronchoscopy, BAL and routine blood sampling following the clinical routine. All participants must sign the informed consent for participation in the study. All analyses to be carried out in this study will not require more human samples than is required by normal clinical practice. The excess amount of biological samples will be destroyed.

Description

Inclusion Criteria:

• All patients of both sexes and over the age of 18 years
• Clinical diagnosis of suspected lung cancer

Exclusion Criteria:

• Patients with infectious diseases,
• Patients with interstitiopathy
• Patients with autoimmune diseases
• Patients with cancers not covered by the inclusion criteria
• subjects on glucocorticoid therapy
• subjects who cannot undergo bronchial biopsy
• subjects who will not sign informed consent.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune checkpoints in COPD and lung cancer.	Measurement of immune checkpoint PD-L1, PD-1, e CTLA-4 levels in all enrolled subjects. The relative expression will be calculated by Real-time PCR using the comparative cycle threshold method (Ct) (2 - ΔΔCt).	The outcome will be measured once for each included patient after the enrollment through study completion, an average of 3 year
Mitochondrial activity in COPD and lung cancer.	Measurement of mitochondrial dysfunction markers in all enrolled subjects. ATP levels will be measured by means of the 'ATP bioluminescence assay kit' and the factors 'PTEN-induced kinase 1 (PINK)-Parkin-mediated pathway' (marker of mitophagy) and sirtuins (marker of senescence) by ELISA assay	The outcome will be measured once for each included patient after the enrollment through study completion, an average of 3 year.
Environmental pollutants in COPD and lung cancer.	Measurement of pollutant concentrations in all enrolled subjects. A fraction of BAL and peripheral blood will be used for the analysis of pollutants deposited on the cell surface and in the supernatant by means of gas chromatography (GC) coupled to mass spectrometry (MS).	The outcome will be measured once for each included patient after the enrollment through study completion, an average of 3 year.
G-quadruplex levels in all enrolled subjects.	Measurement of G-quadruplex levels in all enrolled subjects. The BG4 antibody will be used to evaluate the formation of G-quadruplex structures. Laser scanning confocal microscopy will be performed with a laser scanning confocal microscope with a 400X objective and the signal analysed with Fiji software.	The outcome will be measured once for each included patient after the enrollment through study completion, an average of 3 year.

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Collaborators: Cardarelli Hospital

Publications and helpful links

General Publications

• Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015 Nov;90(2):121-7. doi: 10.1016/j.lungcan.2015.08.017. Epub 2015 Aug 29.
• Wilkinson TMA. Immune checkpoints in chronic obstructive pulmonary disease. Eur Respir Rev. 2017 Jun 28;26(144):170045. doi: 10.1183/16000617.0045-2017. Print 2017 Jun 30.
• Wasen C, Erlandsson MC, Bossios A, Ekerljung L, Malmhall C, Toyra Silfversward S, Pullerits R, Lundback B, Bokarewa MI. Smoking Is Associated With Low Levels of Soluble PD-L1 in Rheumatoid Arthritis. Front Immunol. 2018 Jul 27;9:1677. doi: 10.3389/fimmu.2018.01677. eCollection 2018.
• Prakash YS, Pabelick CM, Sieck GC. Mitochondrial Dysfunction in Airway Disease. Chest. 2017 Sep;152(3):618-626. doi: 10.1016/j.chest.2017.03.020. Epub 2017 Mar 21.
• Sachdeva K, Do DC, Zhang Y, Hu X, Chen J, Gao P. Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence. Front Immunol. 2019 Nov 29;10:2787. doi: 10.3389/fimmu.2019.02787. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: June 19, 2024
• First Submitted That Met QC Criteria: June 25, 2024
• First Posted (Estimated): July 2, 2024

Study Record Updates

• Last Update Posted (Estimated): July 2, 2024
• Last Update Submitted That Met QC Criteria: June 25, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: COPD; Lung cancer; immune checkpoints; Mitochondrial dysfunction; cross-sectional; non-pharmacological; multicenter study; Environmental pollution
• Additional Relevant MeSH Terms: Metabolic Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Mitochondrial Diseases; Lung Neoplasms
• Other Study ID Numbers: MITO2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No