Alveolar Epithelial Regeneration: Various Processes

Introduction

The lung is one of the most important organs of the human body. The lung facilitates the process of gaseous exchange and respiration. As a result, the different tissues of the body get oxygen and carbon dioxide, which is harmful to the body, excreted out of the body. However, the normal lung function is being disrupted by various disease processes. But, it has been observed that lung tissues have the capability to restore their normal form and function to some extent. The remarkable property of repair and regeneration of the lung alveoli helps in this process.

What Is Alveolar Epithelium?

Alveoli are known as the functional unit of the lungs. The cellular lining of the alveoli is known as the alveolar epithelium. This is composed of 90 percent of the lung surface. The cells of the alveolar epithelium are made up of type I and type II cells. Type I cells are called alveolar epithelial cells and are comprised of 96 percent of the surface. Type II cells are known as pneumocytes and only comprise 4 percent of the surface.

1. Type I Alveolar Cells:

These are large squamous epithelial cells. These cells have a cytoplasmic barrier of 50 to 100 nanometers thick that forms an air-blood barrier. These cells share a basement membrane with pulmonary capillary endothelium and help in the gas exchange. Tight gap junctions join these cells. The functions of these cells are:

• Help in the gas exchange.

• These cells are responsible for maintaining ion and fluid balance within the alveoli.

• Induce the type II cells to secrete surfactants.

1. Type II cells:

These cells are large cuboidal cells located at the corner of the alveoli. The volume of these cells is half that of type I cells. The metabolic rate of such cells is really high with the presence of large numbers of mitochondria. These cells are associated with high glucose and oxygen consumption and are responsible for the increased production of lipids. The functions of these cells are:

• Production of pulmonary surfactants is the main function of these cells. These surfactants are helpful in preventing the collapse of the alveoli.

• These cells are helpful in the production of various inflammatory substances, which are useful for cellular defense.

• These cells produce Surfactant proteins A and D, which provide immunity from foreign substances like bacteria, pathogens, and pollutants.

• Sodium and chloride transport is maintained by these cells, which is helpful in maintaining alveolar fluid balance.

What Is the Mechanism of Lung Repair?

The mechanism of lung tissue repair can be subdivided into several groups. Based on the role played by different cells, this can be subdivided into several categories.

• Role of Type II Alveolar Cells:

After the injury, the type II alveolar cells are activated. This activation is done by substances like stem cell antigen 1. These activated type II alveolar cells are called facultative stem cells. These activated type II have a higher rate of proliferation and differentiation. One of the main functions of these cells is transforming into type I cells. At first, the type II cells are differentiated into intermediate cells. These cells are known as damage-associated transition progenitors (DATPs), pre-alveolar type-1 transitional cell state (PATS) or alveolar differentiation intermediate (ADI). The transcriptome (a set of RNA molecules)of these intermediate cells suggested that these are nothing but cell cycle arrest subpopulation of type II cells. Further, these cells are differentiated into type I cells.

The action of several singling molecules also mediates this proliferation and differentiation of type II. Molecules like fibroblast growth factor (a protein that helps in the proliferation of fibroblasts) or endothelial growth factor promote type II cell proliferation. BMP4 (bone morphogenetic protein 4), which is associated with bone formation, induces the transformation of type ii cells to type I cells.

Endothelial cells, immune cells, and fibroblasts also influence the function of type II cells. Sphingosine 1 phosphate (a type of lipid mediator), HGF (hepatocyte growth factor, a type of growth factor), and thrombospondin 1 (a molecule that helps in cellular interaction) are secreted by endothelial cells are responsible for the activation of type II cells. Platelets derived growth factor alpha and Wnt molecules derived from fibroblasts and are responsible for differentiation and proliferation. Immune cells secret factors like tumor necrosis factor-alpha and interleukin one beta. Tumor necrosis factor-alpha is associated with promoting the proliferation of type II cells. Interleukin one beta is the responsible transformation of type II cells via activation of receptor IL1R.

• The Role of Type I Cells:

Plasticity is a cellular mechanism through which one cell can be differentiated into another cell. Type I cells also show some amount of plasticity. Only 5 percent of type I cells show cellular transdifferentiation. Such plasticity can be seen specifically in cases of hypoxia (low oxygen supply) induced lung disorders or in cases of partial pneumonectomy (surgical removal of a partial portion of lungs). Type I cells proliferate and differentiate into type II cells. Disruption of the Hippo signaling pathway (pathway which controls organ size) causes the inactivation of YAP signaling. This is associated with the transformation of type I cells to type II cells.

• The Role of Airway Cells:

Not only the alveolar epithelial cells but also some other cells of the airway play a crucial role in the process of repair and regeneration. These cells are:

1. Tracheal Basal Cells:

These are pseudostratified epithelial cells that are present in the trachea. Cytokines (inflammatory mediators) and transformation-related proteins are responsible for the renewal of these cells and the differentiation of these cells.

1. Bronchioalveolar-Duct Junction (BADJ) Cells:

The transitional zone between the alveolar zone and the bronchiolar region. Club cells present in this region are known as epithelial progenitor cells. These cells have the self-renewal property and can give rise to the ciliated cells and goblet cells. Variant club (vClub) cells are the neuroendocrine bodies present in the bronchioalveolar duct junction (BADJ) and can differentiate into club cells when these cells are damaged.

What Are the Conditions in Which Alveolar Repair Can Be Seen?

Different pathological conditions are associated with alveolar repair:

1. Idiopathic Pulmonary Fibrosis (IPF): One of the most common disorders causing lung fibrosis.

2. Chronic Obstructive Pulmonary Disorder: A progressive disorder of the obstruction of the airflow.

3. COVID-19-related lung damage.

4. Hypoxia-related lung changes.

Conclusion:

Regeneration and repair of the lung tissues are important physiological properties. This helps to regain the formal functional capabilities of the lung. Several chemical factors are associated with such regenerations. Type II alveolar cells are the primary cells that are responsible for this process.