Fig. 4

Plasma membrane damage and repair in the lung, gastrointestinal tract, skin, vasculature, and bone. Red arrows: sources of plasma membrane damage; black arrows: repair pathways; gray arrows: forms of cellular resistance. Human body was created with BioRender.com. (i) Pneumocytes: Mechanical stress during ventilation is typically alleviated by surfactant. Damage-induced ATP leakage promotes lysosomal exocytosis via P2Y2 receptors. MG53 facilitates repair in type I cells through caveolar endocytosis, although its protective role in type II cells remains unclear. Type II cells likely facilitate resealing through ANXA7-dependent fusion of surfactant granules. During S. aureus infection, pneumocytes evade damage from pore-forming toxin by releasing decoy exosomes enriched in host receptor ADAM10. (ii) Gastric Epithelium: Mucus integrity is compromised during H. pylori infection and by amphiphilic molecules such as NSAIDs and alcohol. Pore formation by VacA disrupts microvilli organization upon CAPN1-mediated cleavage of ezrin. Cholesterol extraction and lipid peroxidation are achieved by virulence factors including cholesterol-α-glucoside transferase (CGT), γ-glutamyl transpeptidase (GGT), and urease (via monochloramine, NH4Cl). Gastric repair includes lysosomal exocytosis and annexins, whereas HSP70 activity alleviates chemical disruptions although its exact role remains unclear. Meanwhile, NSAIDs and alcohol elicit damage through direct interactions with plasma membrane phospholipids or indirectly via oxidative stress. Cytoprotective factors include calpains and prostaglandin E2 (PGE2), the latter of which stimulates bicarbonate (HCO3-) release via SLC26A9 to alleviate acid-induced injury. (iii) Intestinal Epithelium: Enterocytes rid bacterial pore-forming toxins (~ 1–2 nm) through cytoplasm extrusion, preceded by oxidative stress as evident by lipid droplet formation and mitochondrial damage. Pores are also removed through vesicle trafficking events and microvilli shedding. Dietary lectins can lead to microvilli abnormalities and inhibit mucus secretion in goblet cells which is a form of membrane resealing. Other dietary molecules, such as poly-unsaturated fatty acids (PUFA) and undigested gliadin peptide, can promote damage through lipid peroxidation and pyroptosis, respectively. (iv) Keratinocytes: During S. aureus infection, keratinocytes internalize α-toxin pores and release them via exosomes. Resistance is achieved through the filaggrin (FLG)-dependent release of acid sphingomyelinase to reduce the availability of exofacial sphingomyelin, an alternative receptor of α-toxin. Ultraviolet A irradiation causes lipid peroxidation that is alleviated by NRF2-dependent antioxidant defenses. Phospholipase D (PLD) activity promotes vesicle fusion events such as lysosomal exocytosis. Alongside repair, caveolar endocytosis can result in caspase-8-mediated apoptosis. (v) Endothelium: Endothelial cells buffer hemodynamic force through caveolae. Advanced glycation end products (AGEs) entice lipid peroxidation whereas overexpression of receptor for AGEs (RAGE) prevents F-actin remodeling required for resealing. Complement-induced damage triggers the release of von Willebrand factor (VWF) which can limit further complement deposition. (vi) Osteoblasts, Osteocytes: Bone cells experience nanoruptures during locomotion that can be repaired through exocytosis with an apparent role for dietary Vitamin E in limiting further oxidative damage. ATP leakage from the wound site initiates calcium-dependent mechanotransduction in nearby, uninjured cells through P2 receptors