**1. Lung chronic diseases: a brief overview**

The primary function of the lungs is the exchange of gas occurring at the level of alveoli, which are arranged as acini in the lung parenchyma. There is strong need to understand the mechanisms of alveolar maintenance and repair because damage to this region underlies many chronic adult lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory failure in pneumonia, and acute respiratory distress syndrome. Additionally, insufficient development of alveoli results in various neonatal and childhood diseases including bronchopulmonary dysplasia [1]. Despite the pivotal role of the alveoli in the development of lung diseases, the pathogenesis of these various conditions is still largely unknown, and treatment options for patients remain limited.

There is clear evidence that environmental exposures and genetic predisposition contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). IPF is defined as a specific form of progressive chronic fibrotic interstitial pneumonia, that is occurring mainly in older adults, and is limited to the lungs [2]. IPF remains relatively rare, with an estimated incidence of roughly 10 cases per 100,000 personyears. Nonetheless, IPF is a lethal lung disorder with a predicted survival of 3–6 years from the onset of symptoms. Most of the deaths among patients with IPF are due to respiratory failure or complicating comorbidities [3]. The pathogenesis of IPF is

characterized by continuous insults or micro-lesions to the alveolar epithelium, which result in abnormal activation of both epithelial cells and fibroblasts. Finally, there is an alteration in the deposition of collagen, which contributes to the irreversible fibrosis typical of the disease [4]. Various risk factors have been identified in the development of IPF, that can be divided between intrinsic and extrinsic [5]. Intrinsic risk factors include genetics, aging, sex, lung microbiome [6–9], while extrinsic risk factors comprise cigarette smoking, environmental exposures, and air pollution [10, 11]. Moreover, studies of familial clustering of pulmonary fibrosis provided evidence that IPF is associated with genetic susceptibility. Multiple genes can affect alveolar stability, for example, genes encoding surfactant proteins A and C, genes associated with enhanced cell senescence by disruption of telomerase function, with the integrity of the epithelial barrier, and with mutant desmosome proteins [12–15].

Chronic obstructive pulmonary disease (COPD) is another chronic lung pathology, representing a serious and growing global health problem, as it is currently a leading cause of death worldwide [16]. COPD is a disease characterized by irreversible airflow reduction, associated with a decline in lung function and increased inflammatory response [17]. It represents a massive health problem, and it is estimated to affect around 200 million people worldwide, with a projected estimate towards further increase in the near future [18]. COPD is the result of the interaction between genetic susceptibility and environmental factors [19]. A well acknowledged genetic cause is α1-antitrypsin deficiency [20], while among environmental factors cigarette smoking represents the main cause; nonetheless, environmental pollution, occupational exposure to dust and fumes, and exposure to passive smoke can induce an increased risk in non-smokers, as well [21, 22]. Exposure to cigarette smoke, which contains a large number of pro-oxidant molecules [23], causes direct damage to the epithelial cells of the airways, leading to increased inflammation and activation of neutrophils, macrophages and lymphocytes in the airways [24]. There is currently no cure for COPD, but fortunately most symptoms can be treated and controlled mostly pharmacologically, at least delaying its progression and worsening. It represents indeed the most common indication for lung transplantation, that is the only conclusive therapeutic option for severe COPD, particularly in younger patients.
