Cellular mechanisms of alveolar pathology in childhood interstitial lung diseases: current insights from mouse genetics

Abstract

Purpose of review: Childhood interstitial lung diseases (ILDs) are a diverse class of disorders affecting the alveolar gas exchange region that lack specific treatments and are usually fatal. Here, we integrate recent insights into alveolar cell biology with histopathology from well characterized mutations of surfactant-associated genes. We take a reductionist approach by parsing discrete histological features and correlating each to perturbation of a particular function of the alveolar epithelial type II (AT2) cell, the central driver of disease, to generate a working model for the cellular mechanisms of disease pathogenesis.

Recent findings: The application of genetically modified mice and single cell genomics has yielded new insights into lung biology, including the identification of a bipotent alveolar progenitor in development, mapping of adult AT2 stem cells in vivo, and demonstration that latent cooperative interactions with fibroblasts can be pathologically activated by targeted injury of the AT2 cell.

Summary: As we learn more about individual and cooperative roles for alveolar cells in health, we can dissect how perturbations of specific cellular functions contribute to disease in childhood ILDs. We hope our updated model centered around the AT2 cell as the initiator of disease provides a cellular framework that researchers can build upon and revise as they identify the specific molecular signals within and between alveolar cells that mediate the diverse pathologic features, so that targeted pharmacologic and cell-based treatments for patients can ultimately be engineered.

Figure 1. Schematic of canonical AT2 cell functions and proposed perturbations producing pathological features seen in chILD

Distinct AT2 cell functions and proposed dysregulation with surfactant-associated gene mutations (A) The alveolar epithelial type 2 (AT2) cell synthesizes and packages surfactant phospholipid in lamellar bodies prior to secretion into the airspace and assembly into tubular myelin that reduces alveolar surface tension, which is subsequently taken up by alveolar macrophages and AT2 cells and recycled. With ABCA3 or SP-B deficiency, AT2 cells contain abnormal LBs and dense vesicles, and lipo-proteinacious material accumulates in the alveolar spaces. The combination of surfactant deficiency and alveolar proteinosis impair gas exchange. (B) AT2 stem cells are intermittently active in adult alveoli when they self-duplicate and trans-differentiate into AT1 cells, although they do not appear to execute this function in development. Pneumocyte hyperplasia is observed in surfactant associated gene mutations, which we propose results from inappropriate proliferation or failed differentiation of AT2 cells and/or bipotent progenitors. (C) AT2 cells and alveolar fibroblasts maintain intimate connections and exhibit functional interactions during alveolar formation and repair. With ABCA3 or SP-B deficiency, we propose the AT2 cells are perturbed (indicated by lines outside of cell) but not eliminated, and that this directly results in activation of fibroblasts promoting collagen deposition that impairs gas diffusion. (D) The alveolar epithelial monolayer constitutes the functional gas exchange surface. Cholesterol clefts and cellular debris are found in the air sacs with SFTPC mutations that result in a misfolded and toxic protein. We propose this debris reflects widespread AT2 (and perhaps also bipotent progenitor and nascent AT1) cell death from the toxic protein. Abbreviations: AT, alveolar epithelial cell; BP, bipotent alveolar progenitor.

Figure 2

Classes of fixed and variable factors and stages of influence on clinical severity in non-lethal hereditary interstitial lung diseases Abbreviations: BP = bipotent alveolar progenitor; AT1, alveolar epithelial type 1 cell; AT2, alveolar epithelial type 2 cell