Imperfect wound healing sets the stage for chronic diseases

Abstract

Although the age of the genome gave us much insight about how our organs fail with disease, it also suggested that diseases do not arise from mutations alone; rather, they develop as we age. In this Review, we examine how wound healing might act to ignite disease. Wound healing works well when we are younger, repairing damage from accidents, environmental assaults, and battles with pathogens. Yet, with age and accumulation of mutations and tissue damage, the repair process can devolve, leading to inflammation, fibrosis, and neoplastic signaling. We discuss healthy wound responses and how our bodies might misappropriate these pathways in disease. Although we focus predominantly on epithelial-based (lung and skin) diseases, similar pathways might operate in cardiac, muscle, and neuronal diseases.

Figure 1. Healthy wound healing response.

(A) Schematic of wound healing response in a healthy tissue with broad timeline below. Here, a break in the epithelium by damage or infection initiates a clot to stem bleeding and gaps and signal an inflammatory response to eliminate damaged cells and pathogens. The gap is repaired by epithelial cell migration and proliferation, followed by rounds of elimination of damaged cells by extrusion and differentiation into different specialized epithelial cell types. Simultaneously, the underlying stroma contracts to reduce the surface area and secretes extracellular matrix to reinforce and repair the damaged area, and recruit neurons, adipocytes, and vasculature to regenerate the wound site to an approximation of its former state. (B) Schematic graph of epithelial cell numbers over time, as cells proliferate, extrude, differentiate, to repair the site.

Fig. 2. Continuous wound healing in asthma.

(A) Schematic of an asthmatic airway before and after a bronchoconstriction. Amplified smooth muscle becomes hyperresponsive causing tight constriction to asthma triggers, which leads to excess crowding of epithelia and so much extrusion that it essentially creates a wound and excess mucus secretion. The wounding from an asthma attack then causes the inflammatory period and hypersensitivity to infections that cause more attacks. (B) Schematic of continuous wound healing from ongoing asthma attacks, driving cycles of extrusion and proliferation, where mucus amplification can be protective for wounds but, in excess, cause complications for patients.

Fig. 3. Excess differentiation and poor proliferation wound response in fibrosis.

Schematics of a healthy (A) and fibrotic (B) alveolar sacs with capillaries beneath. In (A) healthy numbers of AT2 precursor cells and AT1 cells are lost in fibrosis (B) with cells differentiating and accumulating mesenchymal cells within the interstitial space between the alveolar sacs and capillaries. Here, TGF-ß and increasingly stiff matrix can act as a feed-forward cycle to transdifferentiate epithelial cells into fibroblasts that secrete too much matrix and stiffen it. (C) Schematic graph suggesting a poor response to wounding triggers a loss of epithelial cells over time, with increased mesenchymal cells that secrete and bundle stiff matrix.

Fig. 4. Defective wound response in cancer.

(A, B) Schematics of oncogenically mutated cells with and without a wound response. In (A), some mutated cells may be effectively eliminated by Epithelial Defence Against Cancer (here, H-Ras or Src, blue cells), similar to how crowded, aged cells are eliminated by extrusion (center cell), whereas other cells with oncogenic mutations may accrue within the epithelium (here, KRas, green cells). However, when triggers like smoking, pollution, pathogen infections stimulate a wound healing response (B), oncogenically mutated epithelia (green) may be activated to proliferate without check (left) and extrude aberrantly basally, underneath the epithelium, enabling them to escape, dedifferentiate and metastasize (right). Here, tyrosine kinase inhibitors may target cells with amplified EGFR but not those under strain as they migrate through tight spaces during metastasis. (C) Schematic graph suggesting that wound healing in an oncogenic setting can initiate rounds of proliferation and defective extrusion that fail to return to homeostatic epithelial cell numbers, causing neoplastic properties, as well as fibrosis, inflammation, enhanced cell migration, and poor differentiation, known hallmarks of cancer.