Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery.

Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.

The association between alcohol consumption and pulmonary function: a scoping review.

INTRODUCTION: The health effects of alcohol are well established but the influence on pulmonary function remains debated. Studies indicate that small amounts of alcohol are beneficial and heavy consumption is harmful, suggesting a U-shaped association. Our objective is to determine whether there is an association between alcohol intake and changes in pulmonary function parameters, exploring the potential protective effect of moderate alcohol consumption and the harm caused by heavy drinking. METHODS: A comprehensive search from PubMed, Embase, Cochrane and CINAHL was carried out, and studies were evaluated using the JBI methodological framework for scoping reviews. Two independent reviewers conducted parallel screening and data extraction. A data extraction form was utilised to organise key themes, with qualitative analysis and visual representation of the results. RESULTS: Among 4427 screened abstracts, 179 underwent full-text review, resulting in 30 eligible studies. Of these, 10 showed a negative effect, nine reported no impact, nine exhibited a positive effect and two indicated a nonlinear U-shaped association between alcohol consumption and pulmonary function parameters. CONCLUSION: While the U-shaped curve hypothesis remains unconfirmed by the current literature, there are notable associations. Heavy alcohol consumption appears to negatively affect pulmonary function, while low to moderate intake shows a positive influence in included studies. However, the diversity in study quality, the nonstandardised alcohol intake quantification and the confounding role of smoking challenge definitive conclusions. The need for consistent, long-term international studies is evident to further explore this relationship while addressing the complex interplay between alcohol and smoking.

Mechanical Interactions Between the Upper Airway and the Lungs that Affect the Propensity to Obstructive Sleep Apnea in Health and Chronic Lung Disease.

Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive narrowing and collapse of the upper airways during sleep. It is caused by multiple anatomic and nonanatomic factors but end-expiratory lung volume (EELV) is an important factor as increased EELV can stabilize the upper airway via caudal traction forces. EELV is impacted by changes in sleep stages, body position, weight, and chronic lung diseases, and this article reviews the mechanical interactions between the lungs and upper airway that affect the propensity to OSA. In doing so, it highlights the need for additional research in this area.

Unsupervised lung CT image registration via stochastic decomposition of deformation fields.

We address the problem of lung CT image registration, which underpins various diagnoses and treatments for lung diseases. The main crux of the problem is the large deformation that the lungs undergo during respiration. This physiological process imposes several challenges from a learning point of view. In this paper, we propose a novel training scheme, called stochastic decomposition, which enables deep networks to effectively learn such a difficult deformation field during lung CT image registration. The key idea is to stochastically decompose the deformation field, and supervise the registration by synthetic data that have the corresponding appearance discrepancy. The stochastic decomposition allows for revealing all possible decompositions of the deformation field. At the learning level, these decompositions can be seen as a prior to reduce the ill-posedness of the registration yielding to boost the performance. We demonstrate the effectiveness of our framework on Lung CT data. We show, through extensive numerical and visual results, that our technique outperforms existing methods.

Longitudinal changes in lung function following post-9/11 military deployment in symptomatic veterans.

RATIONALE: Exposure to burn pit smoke, desert and combat dust, and diesel exhaust during military deployment to Southwest Asia and Afghanistan (SWA) can cause deployment-related respiratory diseases (DRRDs) and may confer risk for worsening lung function after return. METHODS: Study subjects were SWA-deployed veterans who underwent occupational lung disease evaluation (n = 219). We assessed differences in lung function by deployment exposures and DRRD diagnoses. We used linear mixed models to assess changes in lung function over time. RESULTS: Most symptomatic veterans reported high intensity deployment exposure to diesel exhaust and burn pit particulates but had normal post-deployment spirometry. The most common DRRDs were deployment-related distal lung disease involving small airways (DDLD, 41%), deployment-related asthma (DRA, 13%), or both DRA/DDLD (24%). Those with both DDLD/DRA had the lowest estimated mean spirometry measurements five years following first deployment. Among those with DDLD alone, spirometry measurements declined annually, adjusting for age, sex, height, weight, family history of lung disease, and smoking. In this group, the forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) ratio declined 0.2% per year. Those with more intense inhalational exposure had more abnormal lung function. We found significantly lower estimated FVC and total lung capacity five years following deployment among active duty participants (n = 173) compared to those in the reserves (n = 26). CONCLUSIONS: More intense inhalational exposures were linked with lower post-deployment lung function. Those with distal lung disease (DDLD) experienced significant longitudinal decline in FEV1/FVC ratio, but other DRRD diagnosis groups did not.

Diaphragmatic dysfunction is associated with postoperative pulmonary complications and phrenic nerve paresis in patients undergoing thoracic surgery.

PURPOSE: We aimed to quantify perioperative changes in diaphragmatic function and phrenic nerve conduction in patients undergoing routine thoracic surgery. METHODS: A prospective observational study was performed in patients undergoing esophageal resection or pulmonary lobectomy. Examinations were carried out the day prior to surgery, 3 days and 10-14 days after surgery. Endpoints for diaphragmatic function included ultrasonographic measurements of diaphragmatic excursion and thickening fraction. Endpoints for phrenic nerve conduction included baseline-to-peak amplitude, peak-to-peak amplitude, and transmission delay. Measurements were assessed on both the surgical side and the non-surgical side of the thorax. RESULTS: Forty patients were included in the study. Significant reductions in diaphragmatic excursion were seen on the surgical side of the thorax for all excursion measures (posterior part of the right hemidiaphragm, p < 0.001; hemidiaphragmatic top point, p < 0.001; change in intrathoracic area, p < 0.001). Significant changes were seen for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.041) on the surgical side. However, significant changes were also seen on the non-surgical side for all phrenic nerve measures (baseline-to-peak amplitude, p < 0.001; peak-to-peak amplitude, p < 0.001; transmission delay, p = 0.022). A postoperative reduction in posterior diaphragmatic excursion of more than 50% was significantly associated with postoperative pulmonary complications (coefficient: 2.69 (95% CI [1.38, 4.01], p < 0.001). CONCLUSION: Thoracic surgery caused a significant unilateral reduction in diaphragmatic excursion on the surgical side of the thorax, which was accompanied by significant changes in phrenic nerve conduction. However, phrenic nerve conduction was also significantly affected on the non-surgical side to a lesser extent, which was not mirrored in diaphragmatic excursion. Our findings suggest that phrenic nerve paresis plays a role in postoperative diaphragmatic dysfunction, which may be a contributing factor in the pathogenesis of postoperative pulmonary complications. CLINICAL TRIALS REGISTRATION NUMBER: NCT04507594.

Longitudinal Follow-Up of Participants With Tobacco Exposure and Preserved Spirometry.

Importance: People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective: To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants: SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures: Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures: The primary outcome was assessment for accelerated decline in lung function (FEV1) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic-defined airway wall thickening or emphysema. Results: Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV1 was -31.3 mL/y for participants with symptomatic TEPS vs -38.8 mL/y for those with asymptomatic TEPS (between-group difference, -7.5 mL/y [95% CI, -16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance: Participants with symptomatic TEPS did not have accelerated rates of decline in FEV1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Circadian regulation of pulmonary disease: the importance of timing.

Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms.

Calcificaciones pulmonares metastásicas, 3 casos clínicos / Metastatic pulmonary calcifications: three clinical cases

Las calcificaciones pulmonares metastásicas, hacen referencia a una enfermedad metabólica, caracterizada por depósitos de calcio en tejido pulmonar sano. La etiología es amplia e incluye enfermedades malignas y benignas, siendo la falla renal la causa más frecuente. Es una condición, que, a pesar de ser frecuente, suele ser subdiagnosticada, por presentar pocos o ningún síntoma. Presentamos tres casos clínicos asociados a enfermedad renal crónica, pre y post trasplante.

Metastatic pulmonary calcifications refer to a metabolic disease, characterized by calcium deposits in healthy lung tissue. The etiology is broad and includes malignant and benign diseases, the kidney failure being the most frequent cause. It is a condition, which, despite being frequent, is usually underdiagnosed, because it presents few or no symptoms. We present three clinical cases associated with pre- and post-transplant kidney disease.

Negative Effects of Chronic High Intake of Fructose on Lung Diseases.

In the modern diet, excessive fructose intake (>50 g/day) had been driven by the increase, in recent decades, of the consumption of sugar-sweetened beverages. This phenomenon has dramatically increased within the Caribbean and Latin American regions. Epidemiological studies show that chronic high intake of fructose related to sugar-sweetened beverages increases the risk of developing several non-communicable diseases, such as chronic obstructive pulmonary disease and asthma, and may also contribute to the exacerbation of lung diseases, such as COVID-19. Evidence supports several mechanisms­such as dysregulation of the renin−angiotensin system, increased uric acid production, induction of aldose reductase activity, production of advanced glycation end-products, and activation of the mTORC1 pathway­that can be implicated in lung damage. This review addresses how these pathophysiologic and molecular mechanisms may explain the lung damage resulting from high intake of fructose.

Associação entre comprometimento pulmonar, fatores de risco e desfechos em pacientes com covid-19 atendidos em hospital de referência na Paraíba / Association between lung involvement, risk factors and outcomes in COVID-19 patients treated at a reference hospital in Paraíba

Objetivo: Avaliar a associação entre o grau de comprometimento pulmonar (CP) na TC de tórax dos pacientes com COVID-19 com fatores de risco e desfechos. Métodos: Estudo observacional e retrospectivo com 284 pacientes com COVID-19. Avaliou-se idade, sexo, quadro clínico, saturação na admissão, fatores de risco, tempo de sinto-mas, porcentagem de CP, tempo de internação em enfermaria, UTI e de IOT, e óbito. Foram divididos três grupos conforme o grau de CP. Resultados: 167 pacientes possuíam comprometimento <25%; 80, 25-50%; e 37, >50%. O grupo com maior comprometimento pulmonar possuía maior idade, mais homens e maior presença de tosse, dispneia e alguma comorbidade. Também apresentou menor saturação à admissão, maior necessidade de IOT, in-ternação em enfermaria ou UTI e maior mortalidade. O CP, IOT e idade foram fatores preditores de mortalidade.Conclusões: O grau de CP aparenta estar significativamente associado a alguns parâmetros clínicos, necessidade de internação, intubação e óbito (AU)

Objective: To assess the association between the degree of lung involvement (LI) on chest CT scans of COVID-19 patients, risk factors and outcomes. Methods: Observational and retrospective study of 284 COVID-19 patients. Age, sex, clinical presentation, oxygen saturation on admission, risk factors, time after symptom onset, percentage of LI, length of stay in ward and ICU, duration of ETI, and death were assessed. 3 groups were created according to the LI. Results: 167 patients had an involvement of <25%; 80, 25-50%; and 37, >50%. The group with gre-ater LI was older, had more males and a higher incidence of cough, dyspnea and some comorbidity. Moreover, the group with greater LI had lower saturation on admission, more ETI, more admissions to the ward or ICU, and higher mortality. LI, ETI and age were predictors of mortality. Conclusion: The degree of LI appears to be significantly associated with some clinical parameters, need for hospitalization, intubation, and death (AU)

Investigating phenotypes of pulmonary COVID-19 recovery: A longitudinal observational prospective multicenter trial.

Background: The optimal procedures to prevent, identify, monitor, and treat long-term pulmonary sequelae of COVID-19 are elusive. Here, we characterized the kinetics of respiratory and symptom recovery following COVID-19. Methods: We conducted a longitudinal, multicenter observational study in ambulatory and hospitalized COVID-19 patients recruited in early 2020 (n = 145). Pulmonary computed tomography (CT) and lung function (LF) readouts, symptom prevalence, and clinical and laboratory parameters were collected during acute COVID-19 and at 60, 100, and 180 days follow-up visits. Recovery kinetics and risk factors were investigated by logistic regression. Classification of clinical features and participants was accomplished by unsupervised and semi-supervised multiparameter clustering and machine learning. Results: At the 6-month follow-up, 49% of participants reported persistent symptoms. The frequency of structural lung CT abnormalities ranged from 18% in the mild outpatient cases to 76% in the intensive care unit (ICU) convalescents. Prevalence of impaired LF ranged from 14% in the mild outpatient cases to 50% in the ICU survivors. Incomplete radiological lung recovery was associated with increased anti-S1/S2 antibody titer, IL-6, and CRP levels at the early follow-up. We demonstrated that the risk of perturbed pulmonary recovery could be robustly estimated at early follow-up by clustering and machine learning classifiers employing solely non-CT and non-LF parameters. Conclusions: The severity of acute COVID-19 and protracted systemic inflammation is strongly linked to persistent structural and functional lung abnormality. Automated screening of multiparameter health record data may assist in the prediction of incomplete pulmonary recovery and optimize COVID-19 follow-up management. Funding: The State of Tyrol (GZ 71934), Boehringer Ingelheim/Investigator initiated study (IIS 1199-0424). Clinical trial number: ClinicalTrials.gov: NCT04416100.

Acute Dyspnea and Hemoptysis in an 84-Year-Old Man With Multiple Comorbidities.

CASE PRESENTATION: An 84-year-old man with an active smoking habit presented to the ED with dyspnea, hemoptysis, and thick phlegm that was difficult to clear. He reported no weight loss, no fever, and no chest pain or dysphonia. He denied both international travel and previous contact with confirmed cases of TB or SARS-CoV-2. He had no known occupational exposures. The patient's personal history included a resolved complete atrioventricular block that required a permanent pacemaker, moderate-to-severe COPD, rheumatoid arthritis (treated with oral prednisone, 2.5 mg/d) and B-chronic lymphocytic leukemia (treated with methotrexate and prophylactic oral supplements of ferrous sulfate). Moreover, he was in medical follow up because of a peptic ulcer, atrophic gastritis, and colonic diverticulosis. The patient also had a history of thoracic surgery after an episode of acute mediastinitis from an odontogenic infection, which required ICU management and temporal tracheostomy.

Addressing Race in Pulmonary Function Testing by Aligning Intent and Evidence With Practice and Perception.

The practice of using race or ethnicity in medicine to explain differences between individuals is being called into question because it may contribute to biased medical care and research that perpetuates health disparities and structural racism. A commonly cited example is the use of race or ethnicity in the interpretation of pulmonary function test (PFT) results, yet the perspectives of practicing pulmonologists and physiologists are missing from this discussion. This discussion has global relevance for increasingly multicultural communities in which the range of values that represent normal lung function is uncertain. We review the underlying sources of differences in lung function, including those that may be captured by race or ethnicity, and demonstrate how the current practice of PFT measurement and interpretation is imperfect in its ability to describe accurately the relationship between function and health outcomes. We summarize the arguments against using race-specific equations as well as address concerns about removing race from the interpretation of PFT results. Further, we outline knowledge gaps and critical questions that need to be answered to change the current approach of including race or ethnicity in PFT results interpretation thoughtfully. Finally, we propose changes in interpretation strategies and future research to reduce health disparities.

Systematic Review of Ozone Effects on Human Lung Function, 2013 Through 2020.

BACKGROUND: Ozone effects on lung function are particularly important to understand in the context of the air pollution-health outcomes epidemiologic literature, given the complex relationships between ozone and other air pollutants with known lung function effects. RESEARCH QUESTION: What has been learned about the association between ozone exposures and lung function from epidemiology studies published from 2013 through 2020? STUDY DESIGN AND METHODS: On March 18, 2018, and September 8, 2020, PubMed was searched using the terms health AND ozone, filtering to articles in English and about humans, from 2013 or later. An additional focused review searching for ozone AND (lung function OR FEV1OR FVC) was performed June 26, 2021. Articles were selected for this review if they reported a specific relationship between a lung function outcome and ozone exposure. RESULTS: Of 3,271 articles screened, 53 ultimately met criteria for inclusion. A systematic review with assessment of potential for bias was conducted, but a meta-analysis was not carried out because of differences in exposure duration and outcome quantification. Consistent evidence exists of small decreases in children's lung function, even associated with very low levels of short-term ozone exposure. The effects on adult lung function from exposure to low-level, short-term ozone are less clear, although ozone-associated decrements may occur in the elderly. Finally, long-term ozone exposure decreases both lung function and lung function growth in children, although few new studies have examined long-term ozone and lung function in adults. INTERPRETATION: Much of this literature involves concentrations below the current US Environmental Protection Agency's National Ambient Air Quality Standard of 70 parts per billion over an 8-h averaging time, suggesting that this current standard may not protect children adequately from ozone-related decrements in lung function.

An Integrative Genomic Strategy Identifies sRAGE as a Causal and Protective Biomarker of Lung Function.

BACKGROUND: There are few clinically useful circulating biomarkers of lung function and lung disease. We hypothesized that genome-wide association studies (GWAS) of circulating proteins in conjunction with GWAS of pulmonary traits represents a clinically relevant approach to identifying causal proteins and therapeutically useful insights into mechanisms related to lung function and disease. STUDY QUESTION: Can an integrative genomic strategy using GWAS of plasma soluble receptor for advanced glycation end-products (sRAGE) levels in conjunction with GWAS of lung function traits identify putatively causal relations of sRAGE to lung function? STUDY DESIGN AND METHODS: Plasma sRAGE levels were measured in 6,861 Framingham Heart Study participants and GWAS of sRAGE was conducted to identify protein quantitative trait loci (pQTL), including cis-pQTL variants at the sRAGE protein-coding gene locus (AGER). We integrated sRAGE pQTL variants with variants from GWAS of lung traits. Colocalization of sRAGE pQTL variants with lung trait GWAS variants was conducted, and Mendelian randomization was performed using sRAGE cis-pQTL variants to infer causality of sRAGE for pulmonary traits. Cross-sectional and longitudinal protein-trait association analyses were conducted for sRAGE in relation to lung traits. RESULTS: Colocalization identified shared genetic signals for sRAGE with lung traits. Mendelian randomization analyses suggested protective causal relations of sRAGE to several pulmonary traits. Protein-trait association analyses demonstrated higher sRAGE levels to be cross-sectionally and longitudinally associated with preserved lung function. INTERPRETATION: sRAGE is produced by type I alveolar cells, and it acts as a decoy receptor to block the inflammatory cascade. Our integrative genomics approach provides evidence for sRAGE as a causal and protective biomarker of lung function, and the pattern of associations is suggestive of a protective role of sRAGE against restrictive lung physiology. We speculate that targeting the AGER/sRAGE axis may be therapeutically beneficial for the treatment and prevention of inflammation-related lung disease.

Pulmonary health effects of wintertime particulate matter from California and China following repeated exposure and cessation.

Epidemiological studies show strong associations between fine particulate matter (PM2.5) air pollution and adverse pulmonary effects. In the present study, wintertime PM2.5 samples were collected from three geographically similar regions-Sacramento, California, USA; Jinan, Shandong, China; and Taiyuan, Shanxi, China-and extracted to form PMCA, PMSD, and PMSX, respectively, for comparison in a BALB/c mouse model. Each of four groups was oropharyngeally administered Milli-Q water vehicle control (50 µL) or one type of PM extract (20 µg/50 µL) five times over two weeks. Mice were necropsied on post-exposure days 1, 2, and 4 and examined using bronchoalveolar lavage (BAL), histopathology, and assessments of cytokine/chemokine mRNA and protein expression. Chemical analysis demonstrated all three extracts contained black carbon, but PMSX contained more sulfates and polycyclic aromatic hydrocarbons (PAHs) associated with significantly greater neutrophil numbers and greater alveolar/bronchiolar inflammation on post-exposure days 1 and 4. On day 4, PMSX-exposed mice also exhibited significant increases in interleukin-1 beta, tumor necrosis factor-alpha, and chemokine C-X-C motif ligands-3 and -5 mRNA, and monocyte chemoattractant protein-1 protein. These combined findings suggest greater sulfate and PAH content contributed to a more intense and progressive inflammatory response with repeated PMSX compared to PMCA or PMSD exposure.

A wrinkle in time: circadian biology in pulmonary vascular health and disease.

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently use the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.