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.