Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with "idiopathic" interstitial lung disease.

BACKGROUND: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD. METHODS: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation. RESULTS: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11. CONCLUSION: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Centering and collaborating with community knowledge systems: piloting a novel participatory modeling approach.

BACKGROUND: Systems science approaches like simulation modeling can offer an opportunity for community voice to shape policies. In the episteme of many communities there are elders, leaders, and researchers who are seen as bearers of historic knowledge and can contextualize and interpret contemporary research using knowledge systems of the community. There is a need for a systematic methodology to collaborate with community Knowledge Bearers and Knowledge Interpreters. In this paper we report the results of piloting a systematic methodology for collaborating with a community Knowledge-Bearer and Knowledge-Interpreter to develop a conceptual model revealing the local-level influences and architecture of systems shaping community realities. The use case for this pilot is 'persistent poverty' in the United States, specifically within the inner-city African American community in Baltimore City. METHODS: This pilot of a participatory modeling approach was conducted over a span of 7 sessions and included the following steps, each with an associated script: Step 1: Knowledge-Bearer and Knowledge-Interpreter recruitment Step 2: Relationship building Step 3: Session introduction, Vignette development & enrichment Step 4: Vignette analysis & constructing architecture of systems map Step 5: Augmenting architecture of systems map RESULTS: Each step of the participatory modeling approach resulted in artifacts that were valuable for both the communities and the research effort. Vignette construction resulted in narratives representing a spectrum of lived experiences, trajectories, and outcomes within a community. The collaborative analysis of vignettes yielded the Architecture of Systemic Factors map, that revealed how factors inter-relate to form a system in which lived experience of poverty occurs. A literature search provided an opportunity for the community to contextualize existing research about them using realities of lived experience. CONCLUSION: This methodology showed that a community Knowledge Bearer can function as communicators and interpreters of their community's knowledge base, can develop coherent narratives of lived experiences within which research and knowledge is contextualized, and can collaboratively construct conceptual mappings necessary for simulation modeling. This participatory modeling approach showed that even if there already exists a vast body of research about a community, collaborating with community gives context to that research and brings together disparate findings within narratives of lived experience.

Pathophysiologic Basis of Connected Health Systems.

Since the start of the COVID-19 pandemic, there has been a rapid transition to telehealth across the United States, primarily involving virtual clinic visits. Additionally, the proliferation of consumer technologies related to health reveals that for many people health and care in the contemporary world extends beyond the boundaries of a clinical interaction and includes sensors and devices that facilitate health in personal environments. The ideal connected environment is networked and intelligent, personalized to promote health and prevent disease. The combination of sensors, devices, and intelligence constitutes a connected health system around an individual that is optimized to improve and maintain health, deliver care, and predict and reduce risk of illness. Just as modern medicine uses the pathophysiology of disease as a framework for the basis of pharmacologic therapy, a similar clinically reasoned approach can be taken to organize and architect technological elements into therapeutic systems. In this work, we introduce a systematic methodology for the design of connected health systems grounded in the pathophysiologic basis of disease. As the digital landscape expands with the ubiquity of health devices, it is pivotal to enable technology-agnostic clinical reasoning to guide the integration of technological innovations into systems of health and care delivery that extend beyond the boundaries of a clinical interaction. Applying clinical reasoning in a repeatable and systematic way to organizing technology into therapeutic systems can yield potential benefits including expanding the study of digital therapeutics from individual devices to networked technologies as therapeutic interventions; empowering physicians who are not technological experts to still play a significant role in using clinical reasoning for architecting therapeutic networks of sensors and devices; and developing platforms to catalog and share combinations of technologies that can form therapeutic networks and connected health systems.

Validity and repeatability of cardiopulmonary exercise testing in interstitial lung disease.

BACKGROUND: Cardiopulmonary exercise testing (CPET), and its primary outcome of peak oxygen uptake (VO2peak), are acknowledged as biomarkers in the diagnostic and prognostic management of interstitial lung disease (ILD). However, the validity and repeatability of CPET in those with ILD has yet to be fully characterised, and this study fills this evidence gap. METHODS: Twenty-six people with ILD were recruited, and 21 successfully completed three CPETs. Of these, 17 completed two valid CPETs within a 3-month window, and 11 completed two valid CPETs within a 6-month window. Technical standards from the European Respiratory Society established validity, and repeatability was determined using mean change, intraclass correlation coefficient and typical error. RESULTS: Every participant (100%) who successfully exercised to volitional exhaustion produced a maximal, and therefore valid, CPET. Approximately 20% of participants presented with a plateau in VO2, the primary criteria for establishing a maximal effort. The majority of participants otherwise presented with secondary criteria of respiratory exchange ratios in excess of 1.05, and maximal heart rates in excess of their predicted values. Repeatability analyses identified that the typical error (expressed as percent of coefficient of variation) was 20% over 3-months in those reaching volitional exhaustion. CONCLUSION: This work has, for the first time, fully characterised how patients with ILD respond to CPET in terms of primary and secondary verification criteria, and generated novel repeatability data that will prove useful in the assessment of disease progression, and future evaluation of therapeutic regimens where VO2peak is used as an outcome measure.

Designing a Framework for Remote Cancer Care Through Community Co-design: Participatory Development Study.

BACKGROUND: Recent shifts to telemedicine and remote patient monitoring demonstrate the potential for new technology to transform health systems; yet, methods to design for inclusion and resilience are lacking. OBJECTIVE: The aim of this study is to design and implement a participatory framework to produce effective health care solutions through co-design with diverse stakeholders. METHODS: We developed a design framework to cocreate solutions to locally prioritized health and communication problems focused on cancer care. The framework is premised on the framing and discovery of problems through community engagement and lead-user innovation with the hypothesis that diversity and inclusion in the co-design process generate more innovative and resilient solutions. Discovery, design, and development were implemented through structured phases with design studios at various locations in urban and rural Kentucky, including Appalachia, each building from prior work. In the final design studio, working prototypes were developed and tested. Outputs were assessed using the System Usability Scale as well as semistructured user feedback. RESULTS: We co-designed, developed, and tested a mobile app (myPath) and service model for distress surveillance and cancer care coordination following the LAUNCH (Linking and Amplifying User-Centered Networks through Connected Health) framework. The problem of awareness, navigation, and communication through cancer care was selected by the community after framing areas for opportunity based on significant geographic disparities in cancer and health burden resource and broadband access. The codeveloped digital myPath app showed the highest perceived combined usability (mean 81.9, SD 15.2) compared with the current gold standard of distress management for patients with cancer, the paper-based National Comprehensive Cancer Network Distress Thermometer (mean 74.2, SD 15.8). Testing of the System Usability Scale subscales showed that the myPath app had significantly better usability than the paper Distress Thermometer (t63=2.611; P=.01), whereas learnability did not differ between the instruments (t63=-0.311; P=.76). Notable differences by patient and provider scoring and feedback were found. CONCLUSIONS: Participatory problem definition and community-based co-design, design-with methods, may produce more acceptable and effective solutions than traditional design-for approaches.

Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.

Galectin (Gal)-3 is a profibrotic ß-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 (C max) values ranging from 0.6 to 3 h and a plasma half-life (T 1/2) 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.

Massive pulmonary embolism in patients with extreme bleeding risk: a case series on the successful use of ultrasound-assisted, catheter directed thrombolysis in a district general hospital.

Massive pulmonary embolism (PE), characterised by profound arterial hypotension, is a life-threatening emergency with a 90-day mortality of over 50%. Systemic thrombolysis can significantly reduce the risk of death or cardiovascular collapse in these patients, by around 50%, but these benefits are offset by a fivefold increased risk of intracranial haemorrhage and major bleeding, which may limit its use in patients at high risk of catastrophic haemorrhage. We describe a case series of 3 patients presenting with massive PE, each with extreme risk of bleeding and contra-indication to systemic thrombolysis, treated successfully with ultrasound-assisted, catheter directed thrombolysis (U-ACDT). Our experience of this novel technique using the EkoSonic Endovascular System (Ekos, BTG, London, UK) on carefully selected patients has demonstrated the potential to improve clinical status in shocked patients, with minimal bleed risk. There have been several clinical studies evaluating the Ekos system. Both the ULTIMA and SEATTLE II studies have shown significant reductions in RV/LV ratio by CT scanning when compared to standard anticoagulation in patients with intermediate-risk PE, with minimal bleeding complications. However, there is a pressing need for a randomised trial demonstrating improvement in robust clinical outcomes when comparing U-ACDT to simple anticoagulation. We believe that this case series adds new insight and highlights the potential of catheter directed thrombolysis in this high-risk patient cohort and consideration should be made to its use in cases where systemic thrombolysis is felt to be too high risk.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Respiratory follow-up of patients with COVID-19 pneumonia.

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.

Does the evidence justify routine transfer of residents of aged care facilities for CT scan after minor head trauma?

BACKGROUND: In 2014, the South Australian coroner recommended that residents of residential aged care facilities (RACF) who had sustained a head injury should be transported to emergency departments (ED) for assessment and a head CT scan, with the view to preventing mortality. The evidence base for the recommendation is unclear. AIMS: To determine the rate of emergent intervention (neurosurgery, transfusion of blood products or reversal of anti-coagulation) in residents transferred to ED with minor head trauma who had their usual cognitive function on ED assessment. METHODS: This was a retrospective cohort study by medical records review at two university-affiliated community ED. Participants were patients from RACF attending ED who had suffered minor head trauma and had their usual cognitive function. Exclusions were altered conscious state, new neurological findings or associated orthopaedic injury requiring hospital admission. The primary outcome was rate of emergent intervention in residents transferred to ED with minor head trauma who had their usual cognitive function on ED assessment. RESULTS: A total of 366 patients was studied; median age 86 years, 45% taking anti-coagulant/anti-platelet medication. Eighty per cent underwent head CT. Six per cent had intracranial haemorrhage (ICH; 95% CI 4-8.9%). No patient underwent neurosurgery. One had emergent intervention, reversal of anti-coagulation (0.3%, 95% CI 0.05-1.5%). CONCLUSION: The rate of emergent intervention for ICH in patients from RACF who sustained a minor head trauma but had their normal cognitive function was <1%. None underwent neurosurgical intervention. The low rate of intervention seriously challenges the appropriateness of routine transfer and CT for this patient group.

UK trainee experience in interstitial lung disease: results from a British Thoracic Society survey.

Interstitial lung disease (ILD) is a growing field of respiratory medicine in which novel therapies are emerging. It is important that trainees gain competence and confidence in this area. To explore the training experiences of specialty trainees, we conducted a survey of their practical experience and confidence in diagnosing and managing ILD.

Atomic Fock state preparation using Rydberg blockade.

We use coherent excitation of 3-16 atom ensembles to demonstrate collective Rabi flopping mediated by Rydberg blockade. Using calibrated atom number measurements, we quantitatively confirm the expected √N Rabi frequency enhancement to within 4%. The resulting atom number distributions are consistent with an essentially perfect blockade. We then use collective Rabi π pulses to produce N=1, 2 atom number Fock states with fidelities of 62% and 48%, respectively. The N=2 Fock state shows the collective Rabi frequency enhancement without corruption from atom number fluctuations.

The effect of tenotomy, neurotomy, and dual injury on mouse rotator cuff muscles: Consequences for the mouse as a preclinical model.

A common animal model of muscle pathology following rotator cuff tear (RCT) is a tenotomy of the supraspinatus and infraspinatus, often combined with neurotomy of the suprascapular nerve, which induces a more robust atrophy response than tenotomy alone. However, the utility of this model depends on its similarity to human muscle pathology post-RCT, both in terms of the disease phenotype and mechanisms of muscle atrophy and fatty infiltration. Given the clinical prevalence of nerve injury is low and the muscular response to denervation is distinct from mechanical unloading in other models, an understanding of the biological influence of the nerve injury is critical for interpreting data from this RCT model. We evaluated the individual and combined effect of tenotomy and neurotomy across multiple biological scales, in a robust time-series in the mouse supraspinatus. Muscle composition, histological, and gene expression data related to muscle atrophy, degeneration-regeneration, fatty infiltration, and fibrosis were evaluated. Broadly, we found tenotomy alone caused small, transient changes in these pathological features, which resolved over the course of the study, while neurotomy alone caused a significant fatty atrophy phenotype. The dual injury group had a similar fatty atrophy phenotype to the neurotomy group, though the addition of tenotomy did marginally enhance the fat and connective tissue. Overall, these results suggest the most clinically relevant injury model, tenotomy alone, does not produce a clinically relevant phenotype. The dual injury model partially recapitulates the human condition, but it does so through a nerve injury, which is not well justified clinically.

Supporting self-management for patients with Interstitial Lung Diseases: Utility and acceptability of digital devices.

INTRODUCTION: Patients diagnosed with Interstitial Lung Diseases (ILD) use devices to self-monitor their health and well-being. Little is known about the range of devices, selection, frequency and terms of use and overall utility. We sought to quantify patients' usage and experiences with home digital devices, and further evaluate their perceived utility and barriers to adaptation. METHODS: A team of expert clinicians and patient partners interested in self-management approaches designed a 48-question cross-sectional electronic survey; specifically targeted at individuals diagnosed with ILD. The survey was critically appraised by the interdisciplinary self-management group at Royal Devon University Hospitals NHS Foundation Trust during a 6-month validation process. The survey was open for participation between September 2021 and December 2022, and responses were collected anonymously. Data were analysed descriptively for quantitative aspects and through thematic analysis for qualitative input. RESULTS: 104 patients accessed the survey and 89/104 (86%) reported a diagnosis of lung fibrosis, including 46/89 (52%) idiopathic pulmonary fibrosis (IPF) with 57/89 (64%) of participants diagnosed >3 years and 59/89 (66%) female. 52/65(80%) were in the UK; 33/65 (51%) reported severe breathlessness medical research council MRC grade 3-4 and 32/65 (49%) disclosed co-morbid arthritis or joint problems. Of these, 18/83 (22%) used a hand- held spirometer, with only 6/17 (35%) advised on how to interpret the readings. Pulse oximetry devices were the most frequently used device by 35/71 (49%) and 20/64 (31%) measured their saturations more than once daily. 29/63 (46%) of respondents reported home-monitoring brought reassurance; of these, for 25/63 (40%) a feeling of control. 10/57 (18%) felt it had a negative effect, citing fluctuating readings as causing stress and 'paranoia'. The most likely help-seeking triggers were worsening breathlessness 53/65 (82%) and low oxygen saturation 43/65 (66%). Nurse specialists were the most frequent source of help 24/63 (38%). Conclusion: Patients can learn appropriate technical skills, yet perceptions of home-monitoring are variable; targeted assessment and tailored support is likely to be beneficial.

Regulation of transforming growth factor-ß1-driven lung fibrosis by galectin-3.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a ß-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. OBJECTIVES: To examine the role of galectin-3 in pulmonary fibrosis. METHODS: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: Transforming growth factor (TGF)-ß and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-ß1-induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of ß-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin-3, TD139, blocked TGF-ß-induced ß-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. CONCLUSIONS: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.

Monocytes control second-phase neutrophil emigration in established lipopolysaccharide-induced murine lung injury.

RATIONALE: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. OBJECTIVES: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. METHODS: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2(hi) monocytes. MEASUREMENTS AND MAIN RESULTS: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1(hi) and Gr1(lo) PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. CONCLUSIONS: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.