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Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. P. aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates. P. aeruginosa also causes chronic lung infections in individuals with cystic fibrosis. Multidrug- and totally drug-resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients. The pathogenesis of many P. aeruginosa infections depends on its ability to form biofilms, structured bacterial communities that can coat mucosal surfaces or invasive devices. These biofilms make conditions more favorable for bacterial persistence, as embedded bacteria are inherently more difficult to eradicate than planktonic bacteria. The molecular mechanisms that underlie P. aeruginosa biofilm pathogenesis and the host response to P. aeruginosa biofilms remain to be fully defined. However, it is known that biofilms offer protection from the host immune response and are also extremely recalcitrant to antimicrobial therapy. Therefore, development of novel therapeutic strategies specifically aimed at biofilms is urgently needed. Here, we review the host response, key clinical implications of P. aeruginosa biofilms, and novel therapeutic approaches to treat biofilms relevant to lung infections. Greater understanding of P. aeruginosa biofilms will elucidate novel avenues to improve outcomes for P. aeruginosa pulmonary infections.

The lung microbiome is associated with host immune response and health outcomes in experimental models and patient cohorts. Lung microbiome research is increasing in volume and scope; however, there are no established guidelines for study design, conduct, and reporting of lung microbiome studies. Standardized approaches to yield reliable and reproducible data that can be synthesized across studies will ultimately improve the scientific rigor and impact of published work and greatly benefit microbiome research. In this review, we identify and address several key elements of microbiome research: conceptual modeling and hypothesis framing; study design; experimental methodology and pitfalls; data analysis; and reporting considerations. Finally, we explore possible future directions and research opportunities. Our goal is to aid investigators who are interested in this burgeoning research area and hopefully provide the foundation for formulating consensus approaches in lung microbiome research.

Recent studies have demonstrated that obstructive sleep apnea (OSA) is associated with the development and evolution of nonalcoholic fatty liver disease (NAFLD), independent of obesity or other shared risk factors. Like OSA, NAFLD is a prevalent disorder associated with major adverse health outcomes: Patients with NAFLD may develop cirrhosis, liver failure, and hepatocellular carcinoma. One major finding that has emerged from these studies is that the OSA–NAFLD association is related to the degree of nocturnal hypoxemia in OSA. Animal models have therefore largely focused on intermittent hypoxia, a key manifestation of OSA, to shed light on the mechanisms by which OSA may give rise to the complex metabolic disturbances that are seen in NAFLD. Intermittent hypoxia leads to tissue hypoxia and can result in oxidative stress, mitochondrial dysfunction, inflammation, and overactivation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD. However, many intriguing questions remain unanswered: Principally, how aggressively should the clinician screen for NAFLD in patients with OSA, and vice versa? In this review, we attempt to apply the best evidence from animal and human studies to highlight the relationship between these two disorders and to advocate for further trials aimed at defining these relationships more precisely.

Abstract Traditionally, the presence and severity of obstructive sleep apnea (OSA) have been defined by the apnea–hypopnea index (AHI). Continuous positive airway pressure is generally first-line therapy despite low adherence, because it reliably reduces the AHI when used, and the response to other therapies is variable. However, there is growing appreciation that the underlying etiology (i.e., endotype) and clinical manifestation (i.e., phenotype) of OSA in an individual are not well described by the AHI. We define and review the important progress made in understanding and measuring physiological mechanisms (or endotypes) that help define subtypes of OSA and identify the potential use of genetics to further refine disease classification. This more detailed understanding of OSA pathogenesis should influence clinical treatment decisions as well as help inform research priorities and clinical study design. In short, treatments could be individualized on the basis of the underlying cause of OSA; patients could better understand which symptoms and outcomes will respond to OSA treatment and by how much; and researchers could select populations most likely to benefit from specific treatment approaches for OSA.

Abstract Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.

Abstract Inflammatory bowel diseases (IBDs) are chronic immune-mediated conditions characterized by significant gut tissue damage due to uncontrolled inflammation. Anti-inflammatory treatments have improved, but there are no current prorepair approaches. Organoids have developed into a powerful experimental platform to study mechanisms of human diseases. Here, we specifically focus on its role as a direct tissue repair modality in IBD. We discuss the scientific rationale for this, recent parallel advances in scientific technologies (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 and metabolic programming), and in addition, the clinical IBD context in which this therapeutic approach is tractable. Finally, we review the translational roadmap for the application of organoids and the need for this as a novel direction in IBD. Lay Summary We provide an overview of the translational potential of human intestinal organoids as a prorepair therapy in inflammatory bowel disease. We focus on the key areas of clinical application and the necessary steps toward tangible progress in this novel approach.

In this article, we review the biology and physiological importance of transforming growth factor-β (TGF-β) to homeostasis in the respiratory system, its importance to innate and adaptive immune responses in the lung, and its pathophysiological role in various chronic pulmonary diseases including pulmonary arterial hypertension, chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. The TGF-β family is responsible for initiation of the intracellular signaling pathways that direct numerous cellular activities including proliferation, differentiation, extracellular matrix synthesis, and apoptosis. When TGF-β signaling is dysregulated or essential control mechanisms are unbalanced, the consequences of organ and tissue dysfunction can be profound. The complexities and myriad checkpoints built into the TGF-β signaling pathways provide attractive targets for the treatment of these disease states, many of which are currently being investigated. This review focuses on those aspects of TGF-β biology that are most relevant to pulmonary diseases and that hold promise as novel therapeutic targets.

Abstract Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention.

Since the first publications coining the term RNA-seq (RNA sequencing) appeared in 2008, the number of publications containing RNA-seq data has grown exponentially, hitting an all-time high of 2,808 publications in 2016 (PubMed). With this wealth of RNA-seq data being generated, it is a challenge to extract maximal meaning from these datasets, and without the appropriate skills and background, there is risk of misinterpretation of these data. However, a general understanding of the principles underlying each step of RNA-seq data analysis allows investigators without a background in programming and bioinformatics to critically analyze their own datasets as well as published data. Our goals in the present review are to break down the steps of a typical RNA-seq analysis and to highlight the pitfalls and checkpoints along the way that are vital for bench scientists and biomedical researchers performing experiments that use RNA-seq.

Chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease, interstitial lung disease, and lung cancer, are among the leading causes of morbidity globally and impose major health and financial burdens on patients and society. Effective treatments are scarce, and relevant human model systems to effectively study CLD pathomechanisms and thus discover and validate potential new targets and therapies are needed. Precision-cut lung slices (PCLS) from healthy and diseased human tissue represent one promising tool that can closely recapitulate the complexity of the lung’s native environment, and recently, improved methodologies and accessibility to human tissue have led to an increased use of PCLS in CLD research. Here, we discuss approaches that use human PCLS to advance our understanding of CLD development, as well as drug discovery and validation for CLDs. PCLS enable investigators to study complex interactions among different cell types and the extracellular matrix in the native three-dimensional architecture of the lung. PCLS further allow for high-resolution (live) imaging of cellular functions in several dimensions. Importantly, PCLS can be derived from diseased lung tissue upon lung surgery or transplantation, thus allowing the study of CLDs in living human tissue. Moreover, CLDs can be modeled in PCLS derived from normal lung tissue to mimic the onset and progression of CLDs, complementing studies in end-stage diseased tissue. Altogether, PCLS are emerging as a remarkable tool to further bridge the gap between target identification and translation into clinical studies, and thus open novel avenues for future precision medicine approaches.