Epithelial Cells and Inflammation in Pulmonary Wound Repair

Abstract

Respiratory diseases are frequently characterised by epithelial injury, airway inflammation, defective tissue repair, and airway remodelling. This may occur in a subacute or chronic context, such as asthma and chronic obstructive pulmonary disease, or occur acutely as in pathogen challenge and acute respiratory distress syndrome (ARDS). Despite the frequent challenge of lung homeostasis, not all pulmonary insults lead to disease. Traditionally thought of as a quiescent organ, emerging evidence highlights that the lung has significant capacity to respond to injury by repairing and replacing damaged cells. This occurs with the appropriate and timely resolution of inflammation and concurrent initiation of tissue repair programmes. Airway epithelial cells are key effectors in lung homeostasis and host defence; continual exposure to pathogens, toxins, and particulate matter challenge homeostasis, requiring robust defence and repair mechanisms. As such, the epithelium is critically involved in the return to homeostasis, orchestrating the resolution of inflammation and initiating tissue repair. This review examines the pivotal role of pulmonary airway epithelial cells in initiating and moderating tissue repair and restitution. We discuss emerging evidence of the interactions between airway epithelial cells and candidate stem or progenitor cells to initiate tissue repair as well as with cells of the innate and adaptive immune systems in driving successful tissue regeneration. Understanding the mechanisms of intercellular communication is rapidly increasing, and a major focus of this review includes the various mediators involved, including growth factors, extracellular vesicles, soluble lipid mediators, cytokines, and chemokines. Understanding these areas will ultimately identify potential cells, mediators, and interactions for therapeutic targeting.

Keywords: epithelium; inflammation; injury; lung; regeneration; repair; resolution.

Figure 1

Hallmarks of wound healing and pulmonary epithelial organisation. (A) Upon injury, epithelial cells undergo a multistage process to repair damage. These phases include i. dedifferentiation from specialised and mature cells, ii. adhesion to extracellular matrix, iii. spreading and migration towards the wound site, iv. cellular proliferation and finally v. redifferentiation and repair. (B) Structure of the pulmonary epithelium and organisation of major epithelial cell types.

Figure 2

Pulmonary epithelial cells are quiescent during homeostasis. Staining for Ki67^+ve cells (brown) shows very low proliferation in the mouse airway under basal conditions (A) with an increase in proliferation after airway epithelial injury with naphthalene (B).

Figure 3

Epithelial cells and immune cells engage bidirectional communication to regulate tissue repair. Activated immune cells, including macrophages, neutrophils, and T lymphocytes, regulate epithelial cell responses to promote proliferation, alteration of mediator and cytokine production, and downstream signalling cascades. In turn, injured epithelium can themselves regulate immune cell trafficking and promote a shift from inflammation to resolution and repair functions.

Figure 4

Mechanisms of Wound Healing and opportunities for therapeutic intervention. Epithelial cells regulate and respond to multiple stimuli which have the potential to mediate and promote tissue repair, including apoptotic bodies, microvesicles, lipid mediators, soluble signals, RNAs and miRNAs, and growth factors.