Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

/pdf/autophagy-in-major-human-diseases-5656f0dxta.pdf

Autophagy in major human diseases

Fibrosis progression in the lung commonly results in impaired functional gas exchange, respiratory failure, or even death. In addition to the aberrant activation and differentiation of lung fibroblasts, persistent alveolar injury and incomplete repair are the driving factors of lung fibrotic response. Macrophages are activated and polarized in response to lipopolysaccharide- or bleomycin-induced lung injury. The classically activated macrophage (M1) and alternatively activated macrophage (M2) have been extensively investigated in lung injury, repair, and fibrosis. In the present review, we summarized the current data on monocyte-derived macrophages that are recruited to the lung, as well as alveolar resident macrophages and their polarization, pyroptosis, and phagocytosis in acute lung injury (ALI). Additionally, we described how macrophages interact with lung epithelial cells during lung repair. Finally, we emphasized the role of macrophage polarization in the pulmonary fibrotic response, and elucidated the potential benefits of targeting macrophage in alleviating pulmonary fibrosis.

Macrophages in Lung Injury, Repair, and Fibrosis

Autophagy is a cellular recycling system found in almost all types of eukaryotic organisms. The system is made up of a variety of proteins which function to deliver intracellular cargo to lysosomes for formation of autophagosomes in which the contents are degraded. The maintenance of cellular homeostasis is key in the survival and function of a variety of human cell populations. The interconnection between metabolism and autophagy is extensive, therefore it has a role in a variety of different cell functions. The disruption or dysfunction of autophagy in these cell types have been implicated in the development of a variety of inflammatory diseases including asthma. The role of autophagy in non-immune and immune cells both lead to the pathogenesis of lung inflammation. Autophagy in pulmonary non-immune cells leads to tissue remodeling which can develop into chronic asthma cases with long term effects. The role autophagy in the lymphoid and myeloid lineages in the pathology of asthma differ in their functions. Impaired autophagy in lymphoid populations have been shown, in general, to decrease inflammation in both asthma and inflammatory disease models. Many lymphoid cells rely on autophagy for effector function and maintained inflammation. In stark contrast, autophagy deficient antigen presenting cells have been shown to have an activated inflammasome. This is largely characterized by a TH17 response that is accompanied with a much worse prognosis including granulocyte mediated inflammation and steroid resistance. The cell specificity associated with changes in autophagic flux complicates its targeting for amelioration of asthmatic symptoms. Differing asthmatic phenotypes between TH2 and TH17 mediated disease may require different autophagic modulations. Therefore, treatments call for a more cell specific and personalized approach when looking at chronic asthma cases. Viral-induced lung inflammation, such as that caused by SARS-CoV-2, also may involve autophagic modulation leading to inflammation mediated by lung resident cells. In this review, we will be discussing the role of autophagy in non-immune cells, myeloid cells, and lymphoid cells for their implications into lung inflammation and asthma. Finally, we will discuss autophagy's role viral pathogenesis, immunometabolism, and asthma with insights into autophagic modulators for amelioration of lung inflammation.

/pdf/role-of-autophagy-in-lung-inflammation-5387yz3yfb.pdf

Role of Autophagy in Lung Inflammation.

Organoid models in lung regeneration and cancer

Organoids are derived from stem cells or organ-specific progenitors. They display structures and functions consistent with organs in vivo. Multiple types of organoids, including lung organoids, can be generated. Organoids are applied widely in development, disease modelling, regenerative medicine, and other multiple aspects. Various human pulmonary diseases caused by several factors can be induced and lead to different degrees of lung epithelial injury. Epithelial repair involves the participation of multiple cells and signalling pathways. Lung organoids provide an excellent platform to model injury to and repair of lungs. Here, we review the recent methods of cultivating lung organoids, applications of lung organoids in epithelial repair after injury, and understanding the mechanisms of epithelial repair investigated using lung organoids. By using lung organoids, we can discover the regulatory mechanisms related to the repair of lung epithelia. This strategy could provide new insights for more effective management of lung diseases and the development of new drugs.

/pdf/lung-organoids-useful-tools-for-investigating-epithelial-3ub2jny15i.pdf

Lung organoids, useful tools for investigating epithelial repair after lung injury.

Efficient repair of injured epithelium by airway progenitor cells could prevent acute inflammation from progressing into chronic phase in lung. Here, we used small molecules, genetic loss-of-function, organoid cultures, and in vivo lung-injury models to show that autophagy is essential for maintaining the pool of airway stem-like vClub cells by promoting their proliferation during ovalbumin-induced acute inflammation. Mechanistically, impaired autophagy disrupted glucose uptake in vClub progenitor cells, and either reduced accessibility to glucose or partial inhibition of glycolysis promoted the proliferative capacity of vClub progenitor cells and their daughter Club cells. However, glucose deprivation or glycolysis blockade abrogated the proliferative capacity of airway vClub cells and Club cells but promoted ciliated and goblet cell differentiation. Deficiency of glucose transporter-1 suppressed the proliferative capacity of airway progenitor cells after ovalbumin challenge. These findings suggested that autophagy and glucose metabolism are essential for the maintenance of airway epithelium at steady state and during allergic inflammation.

/pdf/airway-epithelial-regeneration-requires-autophagy-and-40j29hbjhq.pdf

Airway epithelial regeneration requires autophagy and glucose metabolism

Autophagy is a protective cellular mechanism in response to stress conditions. However, whether autophagy is required for maintenance of the alveolar epithelium is unknown. Here, we report that the loss of autophagy-related 5 (Atg5) in AT2 cells worsened bleomycin-induced lung injury. Mechanistically, during bleomycin injury, autophagy downregulated lipid metabolism but upregulated glucose metabolism in AT2 cells for alveolar repair. Chemical blockade of fatty acid synthesis promoted organoid growth of AT2 cells and counteracted the effects of autophagy loss on bleomycin injury. However, genetic loss of glucose transporter 1, interference with glycolysis, or interference with the pentose phosphate pathway reduced the proliferation of AT2 cells. Inhibition of glucose metabolism exacerbated the effects of bleomycin injury. Failure of autophagy generated additional hydrogen peroxide, which reduced AT2 cell proliferation. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration.

Xin Sun

Papers

Airway epithelial regeneration requires autophagy and glucose metabolism

Autophagy Reprograms Alveolar Progenitor Cell Metabolism in Response to Lung Injury