Review

Authors: Hayoung Choi, James D Chalmers

BACKGROUND AND OBJECTIVE

Bronchiectasis exacerbations are significant events in the natural course of the disease and determine long-term clinical outcomes. This review aims to discuss the definition, causes, risk factors, management and prevention of bronchiectasis exacerbations.

METHODS

The PubMed database was searched for relevant articles published in English between January 1990 and March 2022 using keywords "bronchiectasis" and "exacerbation".

KEY CONTENT AND FINDINGS

Causes of bronchiectasis exacerbation are multifactorial; it can be associated with bacterial and viral pathogens, host inflammatory responses, and external environmental effects. In addition, recent advances in bronchiectasis research highlight the phenotype of patients who are more prone to exacerbations, including those with chronic infection, worse symptoms, greater lung inflammation and comorbid airway diseases. Once bronchiectasis exacerbations occur, antibiotics are the mainstay treatment. Preventing exacerbations is of paramount importance because frequent exacerbations are linked to a detrimental disease course and higher mortality. To prevent frequent exacerbations, clinicians should attempt to understand the risk factors for exacerbation that are amenable to therapeutic intervention: so called "treatable traits". Treatments are personalised but include improving mucociliary clearance by physiotherapy and mucoactive therapy, reducing airway infection by inhaled antibiotics, and inflammation by long-term macrolide or in specific subpopulations, inhaled corticosteroids (ICS). Novel approaches to prevent exacerbations including direct anti-inflammatory therapies are in development for bronchiectasis.

CONCLUSIONS

Future research is needed to better manage and prevent exacerbations in patients with bronchiectasis, although recent studies have characterised frequent exacerbator phenotype and enhanced our understanding of various aspects of exacerbations.

PubMed: 36760239
DOI: 10.21037/atm-22-3437

Review

Authors: Alessandro De Angelis, Emma D Johnson, Sivagurunathan Sutharsan...

Bronchiectasis presents a significant challenge due to its rising prevalence, associated economic burden and clinical heterogeneity. This review synthesises contemporary understanding and literature of bronchiectasis exacerbations, addressing the transition from stable state to exacerbations, underlining the importance of early and precise recognition, rigorous severity assessment, prompt treatment, and prevention measures, as well as emphasising the need for strategies to assess and improve early and long-term patient outcomes. The review highlights the interplay between stable state phases and exacerbations in bronchiectasis, introducing the concept of "exogenous and endogenous changes in airways homeostasis" and the "adapted island model" with a particular focus on "frequent exacerbators", a group of patients associated with specific clinical characteristics and worse outcomes. The pathophysiology of exacerbations is explored through the lens of microbial and nonmicrobial triggers and the presence and the activity of comorbidities, elaborating on the impact of both exogenous insults, such as infections and pollution, and endogenous factors such as inflammatory endotypes. Finally, the review proposes a multidisciplinary approach to care, integrating advancements in precision medicine and biomarker research, paving the way for tailored treatments that challenge the traditional antibiotic paradigm.

Topics: Bronchiectasis; Humans; Disease Progression; Risk Factors; Lung; Comorbidity; Prognosis; Anti-Bacterial Agents; Severity of Illness Index; Host-Pathogen Interactions; Treatment Outcome; Inflammation Mediators

PubMed: 39048130
DOI: 10.1183/16000617.0085-2024

Authors: Xiaoye Fan, Tingting Dong, Kun Yan...

The increasing abundance of fine particulate matter (PM2.5) in the environment has increased susceptibility to acute exacerbation of COPD (AECOPD). During PM2.5 exposure, excessive reactive oxygen species (ROS) production triggers a redox imbalance, which contributes to damage to organelles and disruption of homeostasis. At present, there are limited data on whether NOX4/Nrf2 redox imbalance increases susceptibility to acute exacerbation of COPD (AECOPD), and the underlying mechanism is unclear. Therefore, the current study was aimed to evaluate the role of NOX4/Nrf2 redox balance on AECOPD induced by PM2.5-CS-exposure. Here, we report that PM2.5 exacerbates cytotoxicity by enhancing NOX4/Nrf2 redox imbalance-mediated mitophagy. First, exposure to a low-dose of PM2.5 (200 μg/ml) significantly exacerbated oxidative stress and mitochondrial damage by increasing the ROS overproduction, enhancing the excessive NOX4/Nrf2 redox imbalance, decreasing the mitochondrial membrane potential (MMP), and enhancing the mitochondrial fragmentation that were caused by a low-dose of CSE (2.5%). Second, coexposure to PM2.5 and CSE (PM2.5-CSE) induced excessive mitophagy. Third, PM2.5 exacerbated CS-induced COPD, as shown by excessive inflammatory cell infiltration, inflammatory cytokine production and mucus hypersecretion, goblet cell hyperplasia, NOX4/Nrf2 redox imbalance, and mitophagy, these effects triggered excessive ROS production and mitochondrial damage in mice. Mechanistically, PM2.5-CS-induced excessive levels of mitophagy by triggering redox imbalance, leading to greater cytotoxicity and AECOPD; however, reestablishing the NOX4/Nrf2 redox balance via NOX4 blockade or mitochondria-specific ROS inhibitor treatment alleviated this cytotoxicity and ameliorated AECOPD. PM2.5 may exacerbate NOX4/Nrf2 redox imbalance and subsequently enhance mitophagy by increasing the ROS and mito-ROS levels, thereby increasing susceptibility to AECOPD.

Topics: Mice; Animals; Reactive Oxygen Species; NF-E2-Related Factor 2; Mitophagy; Pulmonary Disease, Chronic Obstructive; Particulate Matter; Oxidation-Reduction; NADPH Oxidase 4

PubMed: 36608590
DOI: 10.1016/j.redox.2022.102587

Review

Authors: Jared I Darveaux, Robert F Lemanske

The role of infection in asthma is varied in that it may exacerbate established asthma or contribute to the initial development of the clinical onset of asthma. Mounting evidence implicates both roles with particular viral pathogens, namely human rhinovirus and respiratory syncytial virus, among the most likely culprits in asthma inception. Once asthma is present, infection, particularly viral infection, is a common precipitant of asthma exacerbations. Bacterial infections and colonization also have been associated with exacerbation and recurrent wheeze, an effect that may be independent or a cofactor with viruses. Atypical bacterial infections such as Mycoplasma pneumoniae and Chlamydia pneumoniae and fungi in the case of allergic bronchopulmonary aspergillosis, also play a potential role in inducing and exacerbating this disease. In addition, certain individuals may have a genetic predisposition toward viral-induced wheezing and the development of asthma. This article will discuss host and environmental factors, common pathogens, clinical characteristic, and genetic influences associated with infection-related asthma.

Topics: Animals; Asthma; Bacterial Infections; Comorbidity; Genetic Markers; Genetic Predisposition to Disease; Humans; Lung; Phenotype; Prognosis; Respiratory Tract Infections; Risk Factors; Virus Diseases

PubMed: 25439354
DOI: 10.1016/j.jaip.2014.09.011

Authors: Shaoying Zhang, Dan Wan, Mengchen Zhu...

BACKGROUND AND AIMS

Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear.

APPROACH AND RESULTS

By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen-derived CD11b + cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis.

CONCLUSIONS

CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.

Topics: Mice; Animals; Spleen; Macrophages; Liver; Liver Cirrhosis; Monocytes; Mice, Inbred C57BL

PubMed: 36098707
DOI: 10.1002/hep.32782

Randomized Controlled Trial

Authors: Frank C Sciurba, Stephanie A Christenson, Tara Rheault...

BACKGROUND

Exacerbations in COPD can be life-threatening and can lead to irreversible declines in lung function and quality of life. Medications that reduce exacerbation burden are an unmet need, because exacerbations put patients at risk of more exacerbations and decrease quality of life. Ensifentrine is a first-in-class selective dual inhibitor of phosphodiesterase 3 and 4 with demonstrated nonsteroidal antiinflammatory activity and bronchodilatory effects.

RESEARCH QUESTION

Does ensifentrine reduce the rate or risk of COPD exacerbations?

STUDY DESIGN AND METHODS

A prespecified, pooled analysis of the phase 3 clinical trials Ensifentrine as a Novel Inhaled Nebulized COPD Therapy (ENHANCE)-1 (ClinicalTrials.gov Identifier: NCT04535986) and ENHANCE-2 (ClinicalTrials.gov Identifier: NCT04542057) was conducted to assess the effect of ensifentrine on exacerbation rate and risk (time to first exacerbation). The trials included symptomatic patients aged 40 to 80 years with moderate to severe COPD who received 3 mg twice-daily ensifentrine over 24 weeks or placebo. Subgroup analyses and frequent exacerbator transition risk assessment were conducted post hoc.

RESULTS

In total, 975 patients treated with ensifentrine and 574 patients who received placebo were included in the pooled analysis, including 62% of patients receiving concomitant long-acting muscarinic antagonist or long-acting β-agonist therapy and 18% receiving concomitant inhaled corticosteroid therapy. Ensifentrine was associated with significant reductions in the rate (rate ratio, 0.59; 95% CI, 0.43-0.80; P < .001) and risk (hazard ratio, 0.59; 95% CI, 0.44-0.81; P < .001) of moderate to severe exacerbations compared with placebo. Reductions in the rate and risk of exacerbations generally were consistent across patient subgroups, including age, sex, race, background maintenance medication use, chronic bronchitis, eosinophil count, COPD severity, and exacerbation history. Ensifentrine was associated with a numerical delay in transitioning from an infrequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group B) to a frequent exacerbator (Global Initiative for Chronic Obstructive Lung Disease group E) compared with placebo.

INTERPRETATION

Ensifentrine reduced the rate of exacerbations and increased the time to first exacerbation among patients with COPD across a broad range of clinically relevant subgroups.

Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Female; Aged; Middle Aged; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 3 Inhibitors; Administration, Inhalation; Disease Progression; Bronchodilator Agents; Severity of Illness Index; Adult; Aged, 80 and over; Quality of Life; Isoquinolines; Pyrimidinones

PubMed: 39197510
DOI: 10.1016/j.chest.2024.07.168

Authors: Orestis Katsoulis, Marie Toussaint, Millie M Jackson...

Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.

Topics: Extracellular Traps; Pulmonary Disease, Chronic Obstructive; Animals; Humans; Rhinovirus; Mice; Neutrophils; Male; Female; Picornaviridae Infections; Mice, Inbred C57BL; DNA; Disease Models, Animal; Middle Aged; Inflammation; Aged

PubMed: 38982052
DOI: 10.1038/s41467-024-50197-0

Review

Authors: Joshua W Miller, Andre Smith, Aron M Troen...

BACKGROUND

In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements.

OBJECTIVES

The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians.

RESULTS

Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency.

CONCLUSION

The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Topics: Humans; Vitamin B 12 Deficiency; Folic Acid; Dietary Supplements; Vitamin B 12; Homocysteine; Methylmalonic Acid; Anemia, Pernicious

PubMed: 38987872
DOI: 10.1177/03795721241229503

Authors: Guibin Fang, Xingzhao Wen, Zongrui Jiang...

Osteoarthritis (OA) is the most common joint disease, but no disease-modifying drugs have been approved for OA treatment. Mitophagy participates in mitochondrial homeostasis regulation by selectively clearing dysfunctional mitochondria, which might contribute to cartilage degeneration in OA. Here, we provide evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the several classic mitophagy-regulating pathways and receptors, we found that FUNDC1 plays a key role in preserving chondrocyte homeostasis by inducing mitophagy. FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated mitochondrial dysfunction, exacerbating chondrocyte degeneration and OA progression. FUNDC1 overexpression via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, our study demonstrated that PFKP interacts with and dephosphorylates FUNDC1 to induce mitophagy in chondrocytes. Further analysis identified KD025 as a candidate drug for restoring chondrocyte mitophagy by increasing the FUNDC1-PFKP interaction and thus alleviating cartilage degeneration in mice with DMM-induced OA. Our study highlights the role of the FUNDC1-PFKP interaction in chondrocyte homeostasis via mitophagy induction and identifies KD025 as a promising agent for treating OA by increasing chondrocyte mitophagy.

Topics: Animals; Mice; Mitophagy; Cartilage, Articular; Apoptosis; Osteoarthritis; Chondrocytes; Membrane Proteins; Mitochondrial Proteins

PubMed: 37838829
DOI: 10.1016/j.ymthe.2023.10.016

Authors: Xida Zhao, Jingbo Liu, Chong Zhang...

Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.

Topics: Animals; Colitis, Ulcerative; Mice; Mice, Inbred C57BL; Porphyromonas gingivalis; Protein-Arginine Deiminases; Virulence Factors

PubMed: 34593756
DOI: 10.1038/s41368-021-00136-2