Dent Clin North Am. 2023 Jul;67(3):443-446. doi: 10.1016/j.cden.2023.02.015. Epub 2023 Apr 19.

ABSTRACT

A 15-year-old boy attended Emergency Department with a complaint of difficulty in breathing due to dental infection. A pulmonologist was consulted regarding the severity of the cystic fibrosis. The patient was admitted and intravenous (IV) fluids and antibiotics were given. The infected mandibular right first permanent molar tooth # 30 was extracted under IV ketamine dissociative anesthesia in the hospital setting.

PMID:37244711 | DOI:10.1016/j.cden.2023.02.015

Chest. 2023 May 25:S0012-3692(23)00783-3. doi: 10.1016/j.chest.2023.05.024. Online ahead of print.

ABSTRACT

BACKGROUND: Introduction of novel therapies for cystic fibrosis (CF), raises the question whether traditional treatments can be withdrawn. Nebulized hypertonic saline (HS) could potentially be discontinued in patients receiving Dornase alfa (DA).

RESEARCH QUESTION: In the pre-modulator era, did people with CF who were F508del homozygous (CFF508del) and received DA and HS have better preserved lung function than those treated with DA only?

STUDY DESIGN: Retrospective analysis of CF Foundation Patient Registry data (2006-2014). Among 13,406 CFF508del with data for at least 2 consecutive years, 1,241 CFF508del had spirometry results and were treated with DA for 1-5 years without DA or HS during the preceding (baseline) year. Absolute percent predicted FEV1 (ppFEV1) change while on DA and HS relative to DA only was the main outcome. A marginal structural model was applied to assess the effect of 1-5 years of HS while controlling for time-dependent confounding.

RESULTS: Of 1,241 CFF508del, 619 (median baseline age 14.6 years; IQR 6-53) received DA only and 622 (14.55 years; IQR 6-48.1) were treated with DA and HS for 1-5 years. After 1 year, subjects receiving DA and HS had ppFEV1 that averaged 6.60% lower than ppFEV1 in those treated with DA only (95%CI: -8.54% to -4.66%; P<.001). Lower lung function in the former relative to the latter persisted throughout follow-up, highlighting confounding by indication. After accounting for baseline age, sex, race, DA use duration, baseline and previous year's ppFEV1 and time-varying clinical characteristics, DA and HS for 1-5 years were similar to DA only regarding ppFEV1 (year 1: mean ppFEV1 change +0.53% [95%CI: -0.66% to +1.71%; P=.38]; year 5: -1.82% [-4.01% to +0.36%; P=.10].

INTERPRETATION: In the pre-modulator era, CFF508del had no significant difference in lung function when nebulized HS was added to DA for 1-5 years.

PMID:37244586 | DOI:10.1016/j.chest.2023.05.024

Pharmaceutics. 2023 May 13;15(5):1488. doi: 10.3390/pharmaceutics15051488.

ABSTRACT

Pulmonary drug delivery has long been used for local and systemic administration of different medications used in acute and chronic respiratory diseases. Certain lung diseases, such as cystic fibrosis, rely heavily on chronic treatments, including targeted lung delivery. Pulmonary drug delivery possesses various physiological advantages compared to other delivery methods and is also convenient for the patient to use. However, the formulation of dry powder for pulmonary delivery proves challenging due to aerodynamic restrictions and the lower tolerance of the lung. The aim of this review is to provide an overview of the respiratory tract structure in patients with cystic fibrosis, including during acute and chronic lung infections and exacerbations. Furthermore, this review discusses the advantages of targeted lung delivery, including the physicochemical properties of dry powder and factors affecting clinical efficacy. Current inhalable drug treatments and drugs currently under development will also be discussed.

PMID:37242730 | DOI:10.3390/pharmaceutics15051488

Pharmaceutics. 2023 May 8;15(5):1438. doi: 10.3390/pharmaceutics15051438.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ETI) treatment has potential benefits in lung transplant recipients, including improvements in extrapulmonary manifestations, such as gastrointestinal and sinus disease; however, ivacaftor is an inhibitor of cytochrome P450 3A (CYP3A) and may, therefore, pose a risk for elevated systemic exposure to tacrolimus. The aim of this investigation is to determine the impact of ETI on tacrolimus exposure and devise an appropriate dosing regimen to manage the risk of this drug-drug interaction (DDI). The CYP3A-mediated DDI of ivacaftor-tacrolimus was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach, incorporating CYP3A4 inhibition parameters of ivacaftor and in vitro enzyme kinetic parameters of tacrolimus. To further support the findings in PBPK modeling, we present a case series of lung transplant patients who received both ETI and tacrolimus. We predicted a 2.36-fold increase in tacrolimus exposure when co-administered with ivacaftor, which would require a 50% dose reduction of tacrolimus upon initiation of ETI treatment to avoid the risk of elevated systemic exposure. Clinical cases (N = 13) indicate a median 32% (IQR: -14.30, 63.80) increase in the dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) after starting ETI. These results indicate that the concomitant administration of tacrolimus and ETI may lead to a clinically significant DDI, requiring the dose adjustment of tacrolimus.

PMID:37242680 | DOI:10.3390/pharmaceutics15051438

Pharmaceutics. 2023 Apr 24;15(5):1332. doi: 10.3390/pharmaceutics15051332.

ABSTRACT

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a "combination therapy", produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time.

PMID:37242574 | DOI:10.3390/pharmaceutics15051332

J Pers Med. 2023 May 21;13(5):864. doi: 10.3390/jpm13050864.

ABSTRACT

Primary nasal epithelial cells and culture models are used as important diagnostic, research and drug development tools for several airway diseases. Various instruments have been used for the collection of human nasal epithelial (HNE) cells but no global consensus yet exists regarding the optimal tool. This study compares the efficiency of two cytology brushes (Olympus (2 mm diameter) and Endoscan (8 mm diameter)) in collecting HNE cells. The study involved two phases, with phase one comparing the yield, morphology and cilia beat frequency (CBF) of cells collected from paediatric participants using each of the two brushes. Phase two compared nasal brushing under general anaesthetic and in the awake state, across a wide age range, via the retrospective audit of the use of the Endoscan brush in 145 participants. Results indicated no significant difference in CBF measurements between the two brushes, suggesting that the choice of brush does not compromise diagnostic accuracy. However, the Endoscan brush collected significantly more total and live cells than the Olympus brush, making it a more efficient option. Importantly, the Endoscan brush is more cost-effective, with a notable price difference between the two brushes.

PMID:37241034 | DOI:10.3390/jpm13050864

J Pers Med. 2023 Apr 23;13(5):707. doi: 10.3390/jpm13050707.

ABSTRACT

Nasal polyps (NPs) are rarely reported in childhood and usually represent red flags for systemic diseases, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and immunodeficiencies. The European Position Paper released in 2020 (EPOS 2020) provided a detailed classification and defined the correct diagnostic and therapeutic approaches. We report a one-year experience of a multidisciplinary team, made up of otorhinolaryngologists, allergists, pediatricians, pneumologists and geneticists, with the aim of ensuring a personalized diagnostic and therapeutic management of the pathology. In 16 months of activity, 53 patients were admitted (25 children with chronic rhinosinusitis with polyposis and 28 with antro-choanal polyp). All patients underwent phenotypic and endo-typic assessment, using proper classification tools for nasal pathology (both endoscopic and radiological), as well as adequate cytological definition. An immuno-allergic evaluation was carried out. Pneumologists evaluated any lower airway respiratory disease. Genetic investigations concluded the diagnostic investigation. Our experience enhanced the complexity of children's NPs. A multidisciplinary assessment is mandatory for a targeted diagnostic and therapeutic pathway.

PMID:37240876 | DOI:10.3390/jpm13050707

Life (Basel). 2023 May 11;13(5):1163. doi: 10.3390/life13051163.

ABSTRACT

Malignant pleural effusion is associated with a poor prognosis and, while risk stratification models exist, prior studies have not evaluated pleural fluid resolution and its association with survival. We performed a retrospective review of patients diagnosed with malignant pleural effusion between 2013 and 2017, evaluating patient demographics, pleural fluid and serum composition, and procedural and treatment data using Cox regression analysis to evaluate associations with survival. In total, 123 patients were included in the study, with median survival from diagnosis being 4.8 months. Resolution of malignant pleural fluid was associated with a significant survival benefit, even when accounting for factors such as placement of an indwelling pleural catheter, anti-cancer therapy, pleural fluid cytology, cancer pheno/genotypes, and pleural fluid characteristics. Elevated fluid protein, placement of an indwelling pleural catheter, and treatment with targeted or hormone therapies were associated with pleural fluid resolution. We conclude that the resolution of pleural fluid accumulation in patients with malignant pleural effusion is associated with a survival benefit possibility representing a surrogate marker for treatment of the underlying metastatic cancer. These findings support the need to better understand the mechanism of fluid resolution in patients with malignant pleural effusion as well as the tumor-immune interplay occurring with the malignant pleural space.

PMID:37240808 | DOI:10.3390/life13051163

J Clin Med. 2023 May 20;12(10):3577. doi: 10.3390/jcm12103577.

ABSTRACT

The use of inhaled antibiotics was initially almost exclusively confined to patients with cystic fibrosis (CF). However, it has been extended in recent decades to patients with non-CF bronchiectasis or chronic obstructive pulmonary disease who present with chronic bronchial infection by potentially pathogenic microorganisms. Inhaled antibiotics reach high concentrations in the area of infection, which enhances their effect and enables their long-term administration to defeat the most resistant infections, while minimizing possible adverse effects. New formulations of inhaled dry powder antibiotics have been developed, providing, among other advantages, faster preparation and administration of the drug, as well as avoiding the requirement to clean nebulization equipment. In this review, we analyze the advantages and disadvantages of the different types of devices that allow the inhalation of antibiotics, especially dry powder inhalers. We describe their general characteristics, the different inhalers on the market and the proper way to use them. We analyze the factors that influence the way in which the dry powder drug reaches the lower airways, as well as aspects of microbiological effectiveness and risks of resistance development. We review the scientific evidence on the use of colistin and tobramycin with this type of device, both in patients with CF and with non-CF bronchiectasis. Finally, we discuss the literature on the development of new dry powder antibiotics.

PMID:37240682 | DOI:10.3390/jcm12103577

Int J Mol Sci. 2023 May 13;24(10):8709. doi: 10.3390/ijms24108709.

ABSTRACT

In cystic fibrosis (CF), pulmonary infection with Pseudomonas aeruginosa is a cause of increased morbidity and mortality, especially in patients for whom infection becomes chronic and there is reliance on long-term suppressive therapies. Current antimicrobials, though varied mechanistically and by mode of delivery, are inadequate not only due to their failure to eradicate infection but also because they do not halt the progression of lung function decline over time. One of the reasons for this failure is thought to be the biofilm mode of growth of P. aeruginosa, wherein self-secreted exopolysaccharides (EPSs) provide physical protection against antibiotics and an array of niches with resulting metabolic and phenotypic heterogeneity. The three biofilm-associated EPSs secreted by P. aeruginosa (alginate, Psl, and Pel) are each under investigation and are being exploited in ways that potentiate antibiotics. In this review, we describe the development and structure of P. aeruginosa biofilms before examining each EPS as a potential therapeutic target for combating pulmonary infection with P. aeruginosa in CF, with a particular focus on the current evidence for these emerging therapies and barriers to bringing these therapies into clinic.

PMID:37240055 | DOI:10.3390/ijms24108709

Biomolecules. 2023 Apr 27;13(5):760. doi: 10.3390/biom13050760.

ABSTRACT

Cathepsin G (CatG) is a pro-inflammatory neutrophil serine protease that is important for host defense, and has been implicated in several inflammatory disorders. Hence, inhibition of CatG holds much therapeutic potential; however, only a few inhibitors have been identified to date, and none have reached clinical trials. Of these, heparin is a well-known inhibitor of CatG, but its heterogeneity and bleeding risk reduce its clinical potential. We reasoned that synthetic small mimetics of heparin, labeled as non-saccharide glycosaminoglycan mimetics (NSGMs), would exhibit potent CatG inhibition while being devoid of bleeding risks associated with heparin. Hence, we screened a focused library of 30 NSGMs for CatG inhibition using a chromogenic substrate hydrolysis assay and identified nano- to micro-molar inhibitors with varying levels of efficacy. Of these, a structurally-defined, octasulfated di-quercetin NSGM 25 inhibited CatG with a potency of ~50 nM. NSGM 25 binds to CatG in an allosteric site through an approximately equal contribution of ionic and nonionic forces. Octasulfated 25 exhibits no impact on human plasma clotting, suggesting minimal bleeding risk. Considering that octasulfated 25 also potently inhibits two other pro-inflammatory proteases, human neutrophil elastase and human plasmin, the current results imply the possibility of a multi-pronged anti-inflammatory approach in which these proteases are likely to simultaneously likely combat important conditions, e.g., rheumatoid arthritis, emphysema, or cystic fibrosis, with minimal bleeding risk.

PMID:37238630 | DOI:10.3390/biom13050760

Children (Basel). 2023 Apr 28;10(5):802. doi: 10.3390/children10050802.

ABSTRACT

Bronchial provocation tests, such as the mannitol challenge, can be performed to identify and quantify the severity of bronchial hyperresponsiveness in asthmatic patients. Studies of the mannitol challenge as a monitoring tool in asthmatic children are limited. Our primary aim was to compare the bronchial hyperresponsiveness to mannitol in treatment-naive asthmatic children between baseline and three months after receiving the indicated asthma prophylaxis. Twenty-three asthmatic patients aged 4-16 years were analyzed in this prospective cohort study. All subjects underwent the mannitol challenge at baseline and after three months of treatment with budesonide ± formoterol. The difference in the provocative dose of mannitol to induce a 15% drop in FEV1 (PD15) between baseline and follow-up, as well as its association with the presence of exercise-induced or nocturnal asthma symptoms, were evaluated. The PD15 value increased significantly post-treatment (228.5 mg [4.50-458.15]; p = 0.04). Independently of the evaluation time point, the PD15 values were significantly lower in the presence of nocturnal asthma symptoms (490 mg [122-635] vs. 635 mg [635-635]; p = 0.03), whereas there was no association between the PD15 value and the presence of exercise-induced asthma (p = 0.73). These results suggest that bronchial hyperresponsiveness to mannitol may be a potential monitoring tool in the pediatric asthmatic population, reflecting therapy response in children receiving prophylactic treatment.

PMID:37238350 | DOI:10.3390/children10050802

Children (Basel). 2023 Apr 27;10(5):791. doi: 10.3390/children10050791.

ABSTRACT

The forced expiratory volume in one second (FEV1) is regularly used for the follow-up of patients with non-cystic fibrosis bronchiectasis (nCF-BE). The lung clearance index (LCI), measured by the multiple breath washout test, has been recently proposed as a lung function measure and a potential tool more sensitive than the FEV1 measured by spirometry in assessing airway changes seen on imaging. While several data have been endorsed as a useful endpoint in clinical trials of patients with early or mild CF lung disease and as the main outcome measure in clinical trials with CFTR modulators in children and adolescents with CF, few data are available in the context of non-CF bronchiectasis. The aim of this pilot study was to compare the LCI with the FEV1 as well as the forced vital capacity (FVC), the forced expiratory flow at 25-75% of the FVC (FEF 25-75%), and chest imaging based on the modified Reiff score in patients with primary ciliary dyskinesia (PCD) and non-CF, non-PCD bronchiectasis (PCD-BE and nCFnPCD-BE). Additionally, we compared each test's duration and the preferred technique. Twenty children were included; nine had PCD-BE and eleven had nCFnPCD-BE. The median age was twelve years (ages ranging between five and eighteen years). The median LCI was seven while the median z-scores of the FEV1, FVC, and FEF 25-75% were -0.6, 0, and -0.9, respectively. No significant associations or correlations were observed between LCI, spirometric parameters, or the modified Reiff score. However, nearly half of the population (n = 9) had an abnormal LCI, while only 10% had an abnormal FEV1. A total of 75% of children preferred MBW, despite it lasting five times longer than spirometry. In this paper, the authors suggest that LCI might be useful in a cohort of pediatric patients with PCD-BE and nCFnPCD-BE for detecting early lung function changes during their follow-up. Additionally, MBW seems to be preferred by patients. These data may encourage further studies on this topic.

PMID:37238339 | DOI:10.3390/children10050791

Children (Basel). 2023 Apr 27;10(5):789. doi: 10.3390/children10050789.

ABSTRACT

Tachypnoea in the newborn is common. It may arise from the many causes of the respiratory distress syndrome such as hyaline membrane disease, transient tachypnoea of the newborn, meconium aspiration etc. Congenital heart disease rarely presents with early tachypnoea on day one or two, in contrast to the early presentation of cyanosis, unless there is "pump" (ventricular) failure such as may occur in a cardiomyopathy/myocarditis, or as a result of severe obstruction to either ventricle. Space-occupying lesions within the chest, for example from a diaphragmatic hernia or a congenital cystic adenomatoid malformation, may present with early tachypnoea, as can a metabolic cause resulting in acidosis. The aim of this paper, however, is to focus on infants where the tachypnoea persists or develops beyond the newborn period, at times with minimal signs but occasionally with serious underlying pathology. They include causes that may have originated in the newborn but then persist; for example, arising from pulmonary hypoplasia or polycythemia. Many congenital cardiac abnormalities, particularly those causing left sided obstructive lesions, or those due to an increasing left to right shunt from large communications between the systemic and pulmonary circulations, need be considered. Respiratory causes, for example arising from aspiration, primary ciliary dyskinesia, cystic fibrosis, or interstitial lung disease, may lead to ongoing tachypnoea. Infective causes such as bronchiolitis or infantile wheeze generally are readily recognisable. Finally, there are a few infants who present with persistent tachypnoea over the first few weeks/months of their life who remain well and have normal investigations with the tachypnoea gradually resolving. How should one approach infants with persistent tachypnoea?

PMID:37238337 | DOI:10.3390/children10050789

Bioengineering (Basel). 2023 Apr 25;10(5):512. doi: 10.3390/bioengineering10050512.

ABSTRACT

Conserved omicron RNA (COR) is a 40 base long 99.9% conserved sequence in SARS-CoV-2 Omicron variant, predicted to form a stable stem loop, the targeted cleavage of which can be an ideal next step in controlling the spread of variants. The Cas9 enzyme has been traditionally utilized for gene editing and DNA cleavage. Previously Cas9 has been shown to be capable of RNA editing under certain conditions. Here we investigated the ability of Cas9 to bind to single-stranded conserved omicron RNA (COR) and examined the effect of copper nanoparticles (Cu NPs) and/or polyinosinic-polycytidilic acid (poly I:C) on the RNA cleavage ability of Cas9. The interaction of the Cas9 enzyme and COR with Cu NPs was shown by dynamic light scattering (DLS) and zeta potential measurements and was confirmed by two-dimensional fluorescence difference spectroscopy (2-D FDS). The interaction with and enhanced cleavage of COR by Cas9 in the presence of Cu NPs and poly I:C was shown by agarose gel electrophoresis. These data suggest that Cas9-mediated RNA cleavage may be potentiated at the nanoscale level in the presence of nanoparticles and a secondary RNA component. Further explorations in vitro and in vivo may contribute to the development of a better cellular delivery platform for Cas9.

PMID:37237582 | DOI:10.3390/bioengineering10050512

Sci Data. 2023 May 26;10(1):323. doi: 10.1038/s41597-023-02244-6.

ABSTRACT

The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.

PMID:37237059 | DOI:10.1038/s41597-023-02244-6

J Cyst Fibros. 2023 May 24:S1569-1993(23)00120-0. doi: 10.1016/j.jcf.2023.04.014. Online ahead of print.

ABSTRACT

BACKGROUND: The sweat test using pilocarpine iontophoresis remains the gold standard for diagnosing cystic fibrosis, but access and reliability are limited by specialized equipment and insufficient sweat volume collected from infants and young children. These shortcomings lead to delayed diagnosis, limited point-of-care applications, and inadequate monitoring capabilities.

METHODS: We created a skin patch with dissolvable microneedles (MNs) containing pilocarpine that eliminates the equipment and complexity of iontophoresis. Upon pressing the patch to skin, the MNs dissolve in skin to release pilocarpine for sweat induction. We conducted a non-randomized pilot trial among healthy adults (clinicaltrials.gov, NCT04732195) with pilocarpine and placebo MN patches on one forearm and iontophoresis on the other forearm, followed by sweat collection using Macroduct collectors. Sweat output and sweat chloride concentration were measured. Subjects were monitored for discomfort and skin erythema.

RESULTS: Fifty paired sweat tests were conducted in 16 male and 34 female healthy adults. MN patches delivered similar amounts of pilocarpine into skin (1.1 ± 0.4 mg) and induced equivalent sweat output (41.2 ± 25.0 mg) compared to iontophoresis (1.2 ± 0.7 mg and 43.8 ± 32.3 mg respectively). Subjects tolerated the procedure well, with little or no pain, and only mild transient erythema. Sweat chloride concentration measurements in sweat induced by MN patches (31.2 ± 13.4 mmol/L) were higher compared to iontophoresis (24.0 ± 13.2 mmol/L). Possible physiological, methodological, and artifactual causes of this difference are discussed.

CONCLUSIONS: Pilocarpine MN patches present a promising alternative to iontophoresis to enable increased access to sweat testing for in-clinic and point-of-care applications.

PMID:37236899 | DOI:10.1016/j.jcf.2023.04.014

Mol Aspects Med. 2023 May 24;92:101191. doi: 10.1016/j.mam.2023.101191. Online ahead of print.

ABSTRACT

Fibrosis, or tissue scarring, develops as a pathological deviation from the physiological wound healing response and can occur in various organs such as the heart, lung, liver, kidney, skin, and bone marrow. Organ fibrosis significantly contributes to global morbidity and mortality. A broad spectrum of etiologies can cause fibrosis, including acute and chronic ischemia, hypertension, chronic viral infection (e.g., viral hepatitis), environmental exposure (e.g., pneumoconiosis, alcohol, nutrition, smoking) and genetic diseases (e.g., cystic fibrosis, alpha-1-antitrypsin deficiency). Common mechanisms across organs and disease etiologies involve a sustained injury to parenchymal cells that triggers a wound healing response, which becomes deregulated in the disease process. A transformation of resting fibroblasts into myofibroblasts with excessive extracellular matrix production constitutes the hallmark of disease, however, multiple other cell types such as immune cells, predominantly monocytes/macrophages, endothelial cells, and parenchymal cells form a complex network of profibrotic cellular crosstalk. Across organs, leading mediators include growth factors like transforming growth factor-β and platelet-derived growth factor, cytokines like interleukin-10, interleukin-13, interleukin-17, and danger-associated molecular patterns. More recently, insights into fibrosis regression and resolution of chronic conditions have deepened our understanding of beneficial, protective effects of immune cells, soluble mediators and intracellular signaling. Further in-depth insights into the mechanisms of fibrogenesis can provide the rationale for therapeutic interventions and the development of targeted antifibrotic agents. This review gives insight into shared responses and cellular mechanisms across organs and etiologies, aiming to paint a comprehensive picture of fibrotic diseases in both experimental settings and in human pathology.

PMID:37236017 | DOI:10.1016/j.mam.2023.101191

Sci Adv. 2023 May 26;9(21):eadg5128. doi: 10.1126/sciadv.adg5128. Epub 2023 May 26.

ABSTRACT

An intense, nonresolving airway inflammatory response leads to destructive lung disease in cystic fibrosis (CF). Dysregulation of macrophage immune function may be a key facet governing the progression of CF lung disease, but the underlying mechanisms are not fully understood. We used 5' end centered transcriptome sequencing to profile P. aeruginosa LPS-activated human CF macrophages, showing that CF and non-CF macrophages deploy substantially distinct transcriptional programs at baseline and following activation. This includes a significantly blunted type I IFN signaling response in activated patient cells relative to healthy controls that was reversible upon in vitro treatment with CFTR modulators in patient cells and by CRISPR-Cas9 gene editing to correct the F508del mutation in patient-derived iPSC macrophages. These findings illustrate a previously unidentified immune defect in human CF macrophages that is CFTR dependent and reversible with CFTR modulators, thus providing new avenues in the search for effective anti-inflammatory interventions in CF.

PMID:37235648 | DOI:10.1126/sciadv.adg5128

J Fungi (Basel). 2023 May 18;9(5):586. doi: 10.3390/jof9050586.

ABSTRACT

Between 70 and 80% of Valley fever patients receive one or more rounds of antibiotic treatment prior to accurate diagnosis with coccidioidomycosis. Antibiotic treatment and infection (bacterial, viral, fungal, parasitic) often have negative implications on host microbial dysbiosis, immunological responses, and disease outcome. These perturbations have focused on the impact of gut dysbiosis on pulmonary disease instead of the implications of direct lung dysbiosis. However, recent work highlights a need to establish the direct effects of the lung microbiota on infection outcome. Cystic fibrosis, chronic obstructive pulmonary disease, COVID-19, and M. tuberculosis studies suggest that surveying the lung microbiota composition can serve as a predictive factor of disease severity and could inform treatment options. In addition to traditional treatment options, probiotics can reverse perturbation-induced repercussions on disease outcomes. The purpose of this review is to speculate on the effects perturbations of the host microbiome can have on coccidioidomycosis progression. To do this, parallels are drawn to aa compilation of other host microbiome infection studies.

PMID:37233297 | DOI:10.3390/jof9050586