Increased cancer risk is associated with select dietary factors. Dietary lifestyles can alter systemic acid-base balance over time. Acidogenic diets, which are typically high in animal protein and ...salt and low in fruits and vegetables, can lead to a sub-clinical or low-grade state of metabolic acidosis. The relationship between diet and cancer risk prompts questions about the role of acidosis in the initiation and progression of cancer. Cancer is triggered by genetic and epigenetic perturbations in the normal cell, but it has become clear that microenvironmental and systemic factors exert modifying effects on cancer cell development. While there are no studies showing a direct link between diet-induced acidosis and cancer, acid-base disequilibrium has been shown to modulate molecular activity including adrenal glucocorticoid, insulin growth factor (IGF-1), and adipocyte cytokine signaling, dysregulated cellular metabolism, and osteoclast activation, which may serve as intermediary or downstream effectors of carcinogenesis or tumor promotion. In short, diet-induced acidosis may influence molecular activities at the cellular level that promote carcinogenesis or tumor progression. This review defines the relationship between dietary lifestyle and acid-base balance and discusses the potential consequences of diet-induced acidosis and cancer occurrence or progression.
Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent ...small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (
) values ranging from 0.6 to 3 h and a plasma half-life (
) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study ...aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough.
Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency.
Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole.
A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.
ObjectiveTo explore eating and drinking experiences of patients with idiopathic pulmonary fibrosis (IPF), the impact of any changes associated with their diagnosis and any coping mechanisms developed ...by patients.SettingPulmonary fibrosis support groups around the UK and the regional Interstitial Lung Diseases Clinic, Newcastle upon Tyne.Participants15 patients with IPF (9 men, 6 women), median age 71 years, range (54–92) years, were interviewed. Inclusion criteria included competent adults (over the age of 18 years) with a secure diagnosis of IPF as defined by international consensus guidelines. Patients were required to have sufficient English language competence to consent and participate in an interview. Exclusion criteria were a history of other lung diseases, a history of pre-existing swallowing problem of other causes that may be associated with dysphagia and individuals with significant communication or other memory difficulties that render them unable to participate in an interview.DesignA qualitative study based on semistructured interviews used purpose sampling conducted between February 2021 and November 2021. Interviews were conducted via video videoconferencing call platform or telephone call, transcribed and data coded and analysed using a reflexive thematic analysis.ResultsThree main themes were identified, along with several subthemes, which were: (1) Eating, as such, is no longer a pleasure. This theme mainly focused on the physical and sensory changes associated with eating and drinking and their effects and the subsequent emotional and social impact of these changes; (2) It is something that happens naturally and just try and get on with it. This theme centred on the self-determined strategies employed to manage changes to eating and drinking; and (3) What is normal. This theme focused on patients seeking information to better understand the changes in their eating and drinking and the patients’ beliefs about what has changed their eating and drinking.ConclusionsTo our knowledge, this is the first study to report on IPF patients’ lived experience of eating and drinking changes associated with their diagnosis. Findings demonstrate that some patients have substantial struggles and challenges with eating and drinking, affecting them physically, emotionally and socially. There is a need to provide better patient information for this area and further study.
Mononuclear phagocytes (MPs) including monocytes, macrophages and dendritic cells (DCs) are critical innate immune effectors and initiators of the adaptive immune response. MPs are present in the ...alveolar airspace at steady state, however little is known about DC recruitment in acute pulmonary inflammation. Here we use lipopolysaccharide inhalation to induce acute inflammation in healthy volunteers and examine the impact on bronchoalveolar lavage fluid and blood MP repertoire. Classical monocytes and two DC subsets (DC2/3 and DC5) are expanded in bronchoalveolar lavage fluid 8 h after lipopolysaccharide inhalation. Surface phenotyping, gene expression profiling and parallel analysis of blood indicate recruited DCs are blood-derived. Recruited monocytes and DCs rapidly adopt typical airspace-resident MP gene expression profiles. Following lipopolysaccharide inhalation, alveolar macrophages strongly up-regulate cytokines for MP recruitment. Our study defines the characteristics of human DCs and monocytes recruited into bronchoalveolar space immediately following localised acute inflammatory stimulus in vivo.
Studies of microbiota reveal inter-relationships between the microbiomes of the gut and lungs. This relationship may influence the progression of lung disease, particularly in patients with cystic ...fibrosis (CF), who often experience extraoesophageal reflux (EOR). Despite identifying this relationship, it is not well characterised. Our hypothesis is that the gastric and lung microbiomes in CF are related, with the potential for aerodigestive pathophysiology. We evaluated gastric and sputum bacterial communities by culture and 16S rRNA gene sequencing in 13 CF patients. Impacts of varying levels of bile acids, pepsin and pH on patient isolates of Pseudomonas aeruginosa (Pa) were evaluated. Clonally related strains of Pa and NTM were identified in gastric and sputum samples from patients with symptoms of EOR. Bacterial diversity was more pronounced in sputa compared to gastric juice. Gastric and lung bile and pepsin levels were associated with Pa biofilm formation. Analysis of the aerodigestive microbiomes of CF patients with negative sputa indicates that the gut can be a reservoir of Pa and NTM. This combined with the CF patient's symptoms of reflux and potential aspiration, highlights the possibility of communication between microorganisms of the gut and the lungs. This phenomenon merits further research.
Abstract
Introduction
Dysphagia occurs in multiple respiratory pathophysiologies, increasing the risk of pulmonary complications secondary to aspiration. Reflux associated aspiration and a ...dysregulated lung microbiome is implicated in Idiopathic Pulmonary Fibrosis (IPF), but swallowing dysfunction has not been described. We aimed to explore oropharyngeal swallowing in IPF patients, without known swallowing dysfunction.
Methods
Fourteen consecutive outpatients with a secure diagnosis of IPF were recruited and the 10-item Eating Assessment Tool (Eat 10) used to assess patient perception of swallowing difficulty. Oropharyngeal swallowing was assessed in ten patients using Videofluoroscopy Swallow Studies (VFSS). The studies were rated using validated scales: Penetration-Aspiration Scale (PAS); standardised Modified Barium Swallow Impairment Profile (
MBSImP
).
Results
EAT-10 scores indicated frank swallowing difficulty in 4/14 patients. Videofluoroscopy Studies showed that 3/10 patients had airway penetration, and one aspirated liquid without a cough response. Median
MBSImp
for oral impairment was 5, range 3–7 and pharyngeal impairment 4, range 1–14 indicating, overall mild alteration to swallowing physiology.
Conclusion
We conclude that people with IPF can show a range of swallowing dysfunction, including aspiration into an unprotected airway. To our knowledge, this is the first report on swallowing physiology and safety in IPF. We believe a proportion of this group may be at risk of aspiration. Further work is indicated to fully explore swallowing in this vulnerable group.
A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as ...irreversible.
To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained.
We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV(1) or FEF(25-75); consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor.
There was a significant increase in FEV(1) of median 110 ml (range, -70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up).
This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.
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