Emphases

Chronic lung disease (CLD) is the second leading cause of death worldwide and thus a significant global health problem. Among CLD, chronic obstructive pulmonary disease (COPD), as a single disease, is the fastest growing lung disease and estimated to be the third leading cause of death by 2020. The most important risk factor known for CLD is cigarette smoking and exposure to environmental pollution. Other risk factors include occupational exposures, such as coal dust, airway hyperresponsiveness, or genetic predisposition. CLD severely limits the quality of life of affected patients, and importantly, no effective causal therapy for CLD has been developed thus far.

The maintenance of normal lung function throughout the life of an organism is ensured largely by alveolar epithelial cells, which form a tight functional barrier essential for gas exchange. The alveolar epithelium is composed of alveolar type I (ATI) and type II (ATII) cells. ATII cells are cuboidal secretory cells mainly responsible for surfactant secretion, thus reducing surface tension. In addition, ATII cells have been implicated in a number of processes, such as lung defense mechanisms due to cytokine release and antioxidant production. The squamous ATI cells cover over 95% of the alveolar surface, thereby providing the large surface area for gas exchange. ATII cells supposedly serve as progenitors initiating the restoration of alveolar epithelium in the adult lung, with ATII cells either giving rise to new ATII cells or differentiating into ATI cells. ATII and ATI cells produce and secrete components of the extracellular matrix and growth factors thereof, which facilitates restoration of the interstitium and, subsequently, functional alveolar structure.

Alveolar epithelial cell injury and impaired repair has been linked to several CLD, in particular to idiopathic pulmonary fibrosis (IPF) und COPD. IPF is one of the most common forms of interstitial lung diseases and represents a progressive and lethal disease with unresolved pathogenesis. It is characterized by aggregates of activated myofibroblasts, which promote excessive ECM deposition. Fibroblast accumulation occurs in subepithelial layers, close to areas of injured, hyperplastic and activated alveolar epithelial cells. It is well accepted that repetitive injury and subsequent impaired repair of alveolar epithelial type II (ATII) cells, in the presence or absence of local inflammation, represent a key pathogenic mechanism in IPF, which leads to aberrant growth factor activation and perpetuation of fibrotic transformation. 

In contrast to IPF, COPD is characterized by an impairment of lung function due to loss of functional lung tissue. One major feature that contributes to the gradual loss of lung function in COPD is emphysema. Emphysema is defined as destruction of the parenchymal architecture due to distal airspace enlargement and a rather deactivated or silenced alveolar epithelium. Taken together, lung epithelial cells represent essential cells for normal lung homeostasis and are primarily involved in the development of CLD.