Among the eleven members of the IL-1 family cytokines, the precursors of IL-1a, IL-1b, and IL-33 have relatively long N-terminal pro-sequences of approximately one hundred amino acid residues prior to the N-terminus of the mature forms. Compared to the mature forms secreted from the cell, 80-90% of the primary translation product is in the intracellular compartment in the precursor form. However, the precursors are readily released from cells during infections but also with non-infectious conditions such a hypoxia and trauma. In this setting, the precursors act rapidly as “alarmins” in the absence of a processing mechanism to remove the pro-sequence and generate a mature form. In the case of IL-1a, the release of the precursor activates adjacent cells via receptor-mediated signaling. However, there are no data comparing the specific activity of the IL-1a precursor to the mature form. In the present study, we compared the precursor and mature forms of recombinant human IL-1a, IL-1b and IL-33 proteins on the induction of cytokines from A549 cells as well as from human peripheral blood mononuclear cells (PBMC). Similar to the mature form, the IL-1a precursor was active in inducing IL 6 and TNFa, whereas the precursor forms of IL 1b and IL-33 were not active. On PBMC, precursor and mature IL-1a at 0.04 and 0.2 nano-mole were equally active in inducing IL-6. Given the fact that during necrotic cell death, the IL-1a precursor is released intact and triggers IL-1 receptors on tissue macrophages, these data identify the precursor form of IL-1a as a key player in sterile inflammation.

/pdf/the-interleukin-1a-precursor-is-biologically-active-and-is-3c9d81428w.pdf

The Interleukin-1α Precursor is Biologically Active and is Likely a Key Alarmin in the IL-1 Family of Cytokines

Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

https://www.mdpi.com/1422-0067/21/7/2269/pdf

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Oxidative stress has been linked to various disease states as well as physiological aging. The lungs are uniquely exposed to a highly oxidizing environment and have evolved several mechanisms to attenuate oxidative stress. Idiopathic pulmonary fibrosis (IPF) is a progressive age-related disorder that leads to architectural remodeling, impaired gas exchange, respiratory failure, and death. In this article, we discuss cellular sources of oxidant production, and antioxidant defenses, both enzymatic and nonenzymatic. We outline the current understanding of the pathogenesis of IPF and how oxidative stress contributes to fibrosis. Further, we link oxidative stress to the biology of aging that involves DNA damage responses, loss of proteostasis, and mitochondrial dysfunction. We discuss the recent findings on the role of reactive oxygen species (ROS) in specific fibrotic processes such as macrophage polarization and immunosenescence, alveolar epithelial cell apoptosis and senescence, myofibroblast differentiation and senescence, and alterations in the acellular extracellular matrix. Finally, we provide an overview of the current preclinical studies and clinical trials targeting oxidative stress in fibrosis and potential new strategies for future therapeutic interventions. © 2020 American Physiological Society. Compr Physiol 10:509-547, 2020.

Oxidative Stress in Pulmonary Fibrosis.

COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.

https://journals.physiology.org/doi/pdf/10.1152/ajplung.00126.2020

Thoughts on the alveolar phase of COVID-19.

Acute respiratory distress syndrome (ARDS) is the most severe manifestation of acute lung injury (ALI). In patients who survive the acute injury the process of repair and remodelling may be an independent risk factor determining morbidity and mortality. This review explores recent advances in the field of fibroproliferative ARDS/ALI, with a special emphasis on (a) the primary contributing factors with a focus on cellular and soluble factors, and (b) mechanisms involved in repair and remodelling as they pertain to the importance of cell death, re-population, and matrix deposition. Factors influencing progression to fibroproliferative ARDS vs. resolution and reconstitution of the normal pulmonary parenchymal architecture are poorly understood. Determinants of persistent injury and abnormal repair and remodelling may be profoundly affected by both environmental and genetic factors. Moreover, cumulative evidence suggests that acute inflammation and fibrosis may be in part independent and interactive processes that are autonomously regulated and thus amenable to individual and specific therapy. Although our current understanding of these processes is limited by the inability to accurately replicate the complex human physiology in laboratory settings, it has recently become apparent that the process of repair and remodelling begins early in the course of ARDS/ALI and may be determined by the type of pulmonary injury. Understanding the mechanisms leading to and regulating fibroproliferative changes may contribute to the development of novel early therapeutic interventions in ARDS/ALI patients.

/pdf/advances-in-mechanisms-of-repair-and-remodelling-in-acute-2kk57gtlof.pdf

Advances in mechanisms of repair and remodelling in acute lung injury.

Alveolar type II (ATII) cells inhibit fibroblast proliferation in coculture by releasing or secreting a factor(s) that stimulates fibroblast production of prostaglandin E2 (PGE2). In the present study, we sought to determine the factors released from ATII cells that stimulate PGE2 production in fibroblasts. Exogenous addition of rat IL-1alpha to cultured lung fibroblasts induced PGE2 secretion in a dose-response manner. When fibroblasts were cocultured with rat ATII cells, IL-1alpha protein was detectable in ATII cells and in the coculture medium between days 8 and 12 of culture, correlating with the highest levels of PGE2. Furthermore, under coculture conditions, IL-1alpha gene expression increased in ATII cells (but not fibroblasts) compared with either cell cultured alone. In both mixed species (human fibroblasts-rat ATII cells) and same species cocultures (rat fibroblasts and ATII cells), PGE2 secretion was inhibited by the presence of IL-1 receptor antagonist (IL-1Ra) or selective neutralizing antibody directed against rat IL-1alpha (but not IL-1beta). Conditioned media from cocultures inhibited fibroblast proliferation, and this effect was abrogated by the addition of IL-1Ra. Addition of keratinocyte growth factor (KGF) resulted in an earlier increase in PGE2 secretion and fibroblast inhibition (day 8 of coculture). This effect was inhibited by indomethacin but was not altered by IL-1Ra. We conclude that in this coculture system, IL-1alpha secretion by ATII cells is one factor that stimulates PGE2 production by lung fibroblasts, thereby inhibiting fibroblast proliferation. In addition, these studies demonstrate that KGF enhances ATII cell PGE2 production through an IL-1alpha-independent pathway.

https://www.physiology.org/doi/pdf/10.1152/ajplung.00102.2005

Joshua Portnoy

Papers

Alveolar type II cells inhibit fibroblast proliferation: role of IL-1α