Safely Prescribing Nirmatrelvir and Ritonavir-Avoiding Drug-Drug Interactions.

This Teachable Moment discusses drug-drug interactions with nirmatrelvir and ritonavir (Paxlovid) treatment for COVID-19 and considerations when prescribing.

Gut-lung crosstalk during critical illness.

PURPOSE OF REVIEW: Study of organ crosstalk in critical illness has uncovered complex biological communication between different organ systems, but the role of microbiota in organ crosstalk has received limited attention. We highlight the emerging understanding of the gut-lung axis, and how the largest biomass of the human body in the gut may affect lung physiology in critical illness. RECENT FINDINGS: Disruption of healthy gut microbial communities and replacement by disease-promoting pathogens (pathobiome) generates a maladaptive transmitter of messages from the gut to the lungs, connected via the portal venous and the mesenteric lymphatic systems. Gut barrier impairment allows for microbial translocation (living organisms or cellular fragments) to the lungs. Host-microbiota interactions in the gut mucosa can also impact lung physiology through microbial metabolite secretion or host-derived messengers (hormones, cytokines or immune cells). Clinical examples like the prevention of ventilator-associated pneumonia by selective decontamination of the digestive tract show that the gut-lung axis can be manipulated therapeutically. SUMMARY: A growing body of evidence supports the pathophysiological relevance of the gut-lung axis, yet we are only at the brink of understanding the therapeutic and prognostic relevance of the gut microbiome, metabolites and host-microbe interactions in critical illness.

A Review of Robotic-Assisted Bronchoscopy Platforms in the Sampling of Peripheral Pulmonary Lesions.

Robotic-assisted bronchoscopy is one of the newest additions to clinicians' armamentarium for the biopsy of peripheral pulmonary lesions in light of the suboptimal yields and sensitivities of conventional bronchoscopic platforms. In this article, we review the existing literature pertaining to the feasibility as well as sensitivity of available robotic-assisted bronchoscopic platforms.

Systemic inflammation and protease profile of Afro-Caribbean patients with sepsis.

OBJECTIVES: Sepsis is one of the leading causes of morbidity and mortality within the healthcare system and remains a diagnostic and therapeutic challenge. A major issue in the diagnosis of sepsis is understanding the pathophysiologic mechanism, which revolves around host immune system activation and dysregulated responses. African Americans are more likely to experience severe sepsis with higher mortality rates compared to the general population. This pilot study characterized multiple inflammatory markers and proteases in plasma of primarily African American and Afro-Caribbean patients with mild sepsis. METHODS: Plasma was collected from 16 healthy controls and 15 subjects presenting with sepsis, on admission, and again upon resolution of the signs of sepsis, defined as a resolution of sepsis criteria. Plasma samples were analyzed for cytokines, chemokines, and proteases using multiplex bead assays. RESULTS: Elevated levels of granulocyte colony-stimulating factor, interleukin-10, interleukin-15, interleukin-1 receptor antagonist, interleukin-8, interferon gamma-induced protein 10, monocyte chemoattractant protein-1, matrix metallopeptidase 12, and cathepsin S were identified in plasma from sepsis patients on admission compared to control subjects. Interleukin-6, interleukin-8, granulocyte colony-stimulating factor, and cathepsin S were reduced in sepsis patients upon clinical resolution of sepsis. CONCLUSION: These findings profile the circulating inflammatory cytokines, chemokines, and proteases in African Americans and Afro-Caribbean patients during sepsis. The role of these targets in sepsis needs addressing in this patient population.

Elevated S100A9 expression in chronic rhinosinusitis coincides with elevated MMP production and proliferation in vitro.

Chronic rhinosinusitis (CRS) is a common condition associated with inflammation and tissue remodeling of the nose and paranasal sinuses, frequently occurring with nasal polyps and allergies. Here we investigate inflammation and the protease profile in nasal tissues and plasma from control non-CRS patients and CRS patients. Gene expression for several cytokines, proteases, and antiproteases was quantified in nasal tissue from non-CRS and CRS subjects with nasal polyps. Elevated expression of S100A9, IL1A, MMP3, MMP7, MMP11, MMP25, MMP28, and CTSK was observed in tissue from CRS subjects with nasal polyps compared to control tissue. Tissue protein analysis confirmed elevated levels of these targets compared to controls, and increased MMP3 and MMP7 observed in CRS subjects with nasal polyps compared to CRS subjects without polyps. Plasma concentrations of MMP3 and MMP7 were elevated in the CRS groups compared to controls. The nasal cell line, CCL-30, was exposed to S100A9 protein, resulting in increased MMP3, MMP7, and CTSK gene expression and elevated proliferation. Silencing MMP3 significantly reduced S100A9-mediated cell proliferation. Therefore, the elevated expression of S100A9 and MMPs are observed in CRS nasal tissue and S100A9 stimulated MMP3 responses to contribute to elevated nasal cell proliferation.

Elevated levels of calpain 14 in nasal tissue in chronic rhinosinusitis.

Sinusitis is a common condition associated with inflammation in the sinuses and nasal mucosa. Calpain 14 is highly expressed in the nasal tissues of sinusitis subjects. Calpain 14 is associated with epithelial barrier disruption. https://bit.ly/3fyAwVO.

Should we worry about children's exposure to third-hand by-products generated from electronic nicotine delivery systems?

Children and other individuals sharing spaces with END users frequently become exposed to first-, second- and third-hand chemicals. This editorial discusses the findings from a recent study exploring the impact of third-hand exposure. https://bit.ly/3cogiw0.

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics.

Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment.

Early Experience With Methylprednisolone on SARS-CoV-2 Infection in the African American Population, a Retrospective Analysis.

BACKGROUND: Coronavirus disease-19 (COVID-19) is associated with acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) with high mortality rates. In African American (AA) populations, COVID-19 presentations and outcomes are more severe. NIH and Interim WHO guidelines had suggested against the use of corticosteroids unless in clinical trials until the recent publication of the RECOVERY trial. Here, we analyzed the treatment effect of methylprednisolone on patients with AKI and ARDS during the initial 2 months of COVID-19 and detail the learning effect within our institution. METHODS: Between March 1 and April 30, 2020, 75 AA patients met our inclusion criteria for ARDS and AKI, of which 37 had received corticosteroids. Twenty-eight-day mortality, improvement in PaO2/FiO2 ratio, and renal function were analyzed. The impact of methylprednisolone treatment was assessed with multivariable methods. RESULTS: Survival in the methylprednisolone group reached 51% at 21 days compared to 29% in the non-corticosteroid group (P < .001). Methylprednisolone improved the likelihood of renal function improvement. PaO2/FiO2 ratio in the methylprednisolone group improved by 73% compared to 45% in the non-corticosteroid group (P = .01). Age, gender, BMI, preexisting conditions, and other treatment factors did not show any impact on renal or PaO2/FiO2 ratio improvement. The use of anticoagulants, the month of treatment, and AKI during hospitalization also influenced outcomes. CONCLUSION: In AA COVID-19 positive patients with ARDS and AKI, IV methylprednisolone lowered the incidence of mortality and improved the likelihood of renal and lung function recovery. Further investigation with a randomized control trial of corticosteroids is warranted.

Cigarette smoke exposure reduces leukemia inhibitory factor levels during respiratory syncytial viral infection.

Background: Viral infections are considered a major driving factor of chronic obstructive pulmonary disease (COPD) exacerbations and thus contribute to disease morbidity and mortality. Respiratory syncytial virus (RSV) is a frequently detected pathogen in the respiratory tract of COPD patients during an exacerbation. We previously demonstrated in a murine model that leukemia inhibitory factor (LIF) expression was increased in the lungs during RSV infection. Subduing LIF signaling in this model enhanced lung injury and airway hypersensitivity. In this study, we investigated lung LIF levels in COPD patient samples to determine the impact of disease status and cigarette smoke exposure on LIF expression. Materials and methods: Bronchoalveolar lavage fluid (BALF) was obtained from healthy never smokers, smokers, and COPD patients, by written informed consent. Human bronchial epithelial (HBE) cells were isolated from healthy never smokers and COPD patients, grown at the air-liquid interface and infected with RSV or stimulated with polyinosinic:polycytidylic acid (poly (i:c)). Mice were exposed to cigarette smoke daily for 6 months and were subsequently infected with RSV. LIF expression was profiled in all samples. Results: In human BALF, LIF protein was significantly reduced in both smokers and COPD patients compared to healthy never smokers. HBE cells isolated from COPD patients produced less LIF compared to never smokers during RSV infection or poly (i:c) stimulation. Animals exposed to cigarette smoke had reduced lung levels of LIF and its corresponding receptor, LIFR. Smoke-exposed animals had reduced LIF expression during RSV infection. Two possible factors for reduced LIF levels were increased LIF mRNA instability in COPD epithelia and proteolytic degradation of LIF protein by serine proteases. Conclusions: Cigarette smoke is an important modulator for LIF expression in the lungs. Loss of LIF expression in COPD could contribute to a higher degree of lung injury during virus-associated exacerbations.

Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function.

Rationale: CTSS (cathepsin S) is a cysteine protease that is observed at higher concentrations in BAL fluid and plasma of subjects with chronic obstructive pulmonary disease (COPD). Objectives: To investigate whether CTSS is involved in the pathogenesis of cigarette smoke-induced COPD and determine whether targeting upstream signaling could prevent the disease. Methods: CTSS expression was investigated in animal and human tissue and cell models of COPD. Ctss-/- mice were exposed to long-term cigarette smoke and forced oscillation and expiratory measurements were recorded. Animals were administered chemical modulators of PP2A (protein phosphatase 2A) activity. Measurements and Main Results: Here we observed enhanced CTSS expression and activity in mouse lungs after exposure to cigarette smoke. Ctss-/- mice were resistant to cigarette smoke-induced inflammation, airway hyperresponsiveness, airspace enlargements, and loss of lung function. CTSS expression was negatively regulated by PP2A in human bronchial epithelial cells isolated from healthy nonsmokers and COPD donors and in monocyte-derived macrophages. Modulating PP2A expression or activity, with silencer siRNA or a chemical inhibitor or activator, during acute smoke exposure in mice altered inflammatory responses and CTSS expression and activity in the lung. Enhancement of PP2A activity prevented chronic smoke-induced COPD in mice. Conclusions: Our study indicates that the decrease in PP2A activity that occurs in COPD contributes to elevated CTSS expression in the lungs and results in impaired lung function. Enhancing PP2A activity represents a feasible therapeutic approach to reduce CTSS activity and counter smoke-induced lung disease.

Phospholipid transfer protein and alpha-1 antitrypsin regulate Hck kinase activity during neutrophil degranulation.

Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that phospholipid transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.

Chronic Cigarette Smoke Exposure Subdues PP2A Activity by Enhancing Expression of the Oncogene CIP2A.

Phosphatase activity of the major serine threonine phosphatase, protein phosphatase 2A (PP2A), is blunted in the airways of individuals with chronic obstructive pulmonary disease (COPD), which results in heightened inflammation and proteolytic responses. The objective of this study was to investigate how PP2A activity is modulated in COPD airways. PP2A activity and endogenous inhibitors of PP2A were investigated in animal and cell models of COPD. In primary human bronchial epithelial (HBE) cells isolated from smokers and donors with COPD, we observed enhanced expression of cancerous inhibitor of PP2A (CIP2A), an oncoprotein encoded by the KIAA1524 gene, compared with cells from nonsmokers. CIP2A expression was induced by chronic cigarette smoke exposure in mice that coincided with a reduction in PP2A activity, airspace enlargements, and loss of lung function, as determined by PP2A phosphatase activity, mean linear intercept analysis, and forced expiratory volume in 0.05 second/forced vital capacity. Modulating CIP2A expression in HBE cells by silencing RNA or chemically with erlotinib enhanced PP2A activity, reduced extracellular-signal-regulated kinase phosphorylation, and reduced the responses of matrix metalloproteinases 1 and 9 in HBE cells isolated from subjects with COPD. Enhanced epithelial growth factor receptor responses in cells from subjects with COPD were observed to modulate CIP2A expression levels. Our study indicates that chronic cigarette smoke induction of epithelial growth factor receptor signaling and CIP2A expression can impair PP2A responses that are associated with loss of lung function and enhancement of proteolytic responses. Augmenting PP2A activity by manipulating CIP2A expression may represent a feasible therapeutic approach to counter smoke-induced lung disease.