Lung-delivered IL-10 therapy elicits beneficial effects via immune modulation in organic dust exposure-induced lung inflammation.

Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 µg) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNFα (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11cintCD11b+ monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11cintCD11b+ cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure.

Bile Chemistry During Ex Situ Normothermic Liver Perfusion Does Not Always Predict Cholangiopathy.

BACKGROUND: Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs). METHODS: The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined. RESULTS: In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs. CONCLUSIONS: A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.

Localized Liver Injury During Normothermic Ex Situ Liver Perfusion Has No Impact on Short-term Liver Transplant Outcomes.

BACKGROUND: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized. METHODS: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival. RESULTS: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors (P = 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P < 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P = 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P = 0.75; 95% CI, 0.07-6.62). CONCLUSIONS: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted.

Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium. All the Candida-infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus-infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Current Techniques and Indications for Machine Perfusion and Regional Perfusion in Deceased Donor Liver Transplantation.

Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.

Combined repetitive inhalant endotoxin and collagen-induced arthritis drive inflammatory lung disease and arthritis severity in a testosterone-dependent manner.

Respiratory-related diseases are a leading cause of death in rheumatoid arthritis (RA) and are disproportionately higher in men, which may be attributable to environmental risk factors. Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA). This study aimed to determine whether hormone-dependent differences explained these observations. Arthritis-prone male intact and castrated DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for 5 wk and CIA induction. Arthritis scores and serum pentraxin-2 levels were increased in castrated versus intact mice. In contrast, airway cell influx, lung tissue infiltrates, and lung levels of proinflammatory and profibrotic markers (C5a, IL-33, and matrix metalloproteinases) were reduced in castrated versus intact mice. CIA + LPS-induced lung histopathology changes and the expression of lung autoantigens including malondialdehyde acetaldehyde (MAA)- and citrulline (CIT)-modified proteins and vimentin were reduced in castrated animals. There were no differences in serum anti-MAA or anti-CIT protein antibody (ACPA) levels or serum pentraxin levels between groups. Testosterone replacement led to a reversal of several lung inflammatory/profibrotic endpoints noted earlier in castrated male CIA + LPS-treated mice with testosterone supplementation promoting neutrophil influx, MAA expression, and TNF-α, IL-6, and MMP-9. These findings imply that testosterone contributes to lung and arthritis inflammatory responses following CIA + LPS coexposure, but not to systemic autoantibody responses. The CIA + LPS model provides a paradigm for investigations focused on the mechanistic underpinnings for epidemiologic and phenotypic sex differences in RA-related lung disease.NEW & NOTEWORTHY Our study shows that testosterone acts as a key immunomodulatory hormone contributing to critical features of rheumatoid arthritis (RA)-associated lung disease in the setting of airborne endotoxin (lipopolysaccharide; LPS) exposures and concomitant arthritis induction in mice. The exaggerated airway inflammation observed following combined exposures in male mice was accompanied by increases in profibrotic mediators, netosis, and increased expression of lung autoantigens, all relevant to the pathogenesis of lung disease in arthritis.

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls. METHODS: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression. RESULTS: There was increased intermediate (CD14++CD16+) and nonclassical (CD14+/-CD16++) and decreased classical (CD14++CD16-) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes. CONCLUSIONS: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16+ monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target.

D-dimer Release From Livers During Ex Situ Normothermic Perfusion and After In Situ Normothermic Regional Perfusion: Evidence for Occult Fibrin Burden Associated With Adverse Transplant Outcomes and Cholangiopathy.

BACKGROUND: Deceased donor livers are prone to biliary complications, which may necessitate retransplantation, and we, and others, have suggested that these complications are because of peribiliary vascular fibrin microthrombi. We sought to determine the prevalence and consequence of occult fibrin within deceased donor livers undergoing normothermic ex situ perfusion (NESLiP) and evaluate a role for fibrinolysis. METHODS: D-dimer concentrations, products of fibrin degradation, were assayed in the perfusate of 163 livers taken after 2 h of NESLiP, including 91 that were transplanted. These were related to posttransplant outcomes. Five different fibrinolytic protocols during NESLiP using alteplase were evaluated, and the transplant outcomes of these alteplase-treated livers were reviewed. RESULTS: Perfusate D-dimer concentrations were lowest in livers recovered using in situ normothermic regional perfusion and highest in alteplase-treated livers. D-dimer release from donation after brain death livers was significantly correlated with the duration of cold ischemia. In non-alteplase-treated livers, Cox proportional hazards regression analysis showed that D-dimer levels were associated with transplant survival ( P = 0.005). Treatment with alteplase and fresh frozen plasma during NESLiP was associated with significantly more D-dimer release into the perfusate and was not associated with excess bleeding postimplantation; 8 of the 9 treated livers were free of cholangiopathy, whereas the ninth had a proximal duct stricture. CONCLUSIONS: Fibrin is present in many livers during cold storage and is associated with poor posttransplant outcomes. The amount of D-dimer released after fibrinolytic treatment indicates a significant occult fibrin burden and suggests that fibrinolytic therapy during NESLiP may be a promising therapeutic intervention.

Improved Organ Utilization and Better Transplant Outcomes With In Situ Normothermic Regional Perfusion in Controlled Donation After Circulatory Death.

BACKGROUND: . We evaluated whether the use of normothermic regional perfusion (NRP) was associated with increased organ recovery and improved transplant outcomes from controlled donation after circulatory death (cDCD). METHODS: . This is a retrospective analysis of UK adult cDCD donors' where at least 1 abdominal organ was accepted for transplantation between January 1, 2011, and December 31, 2019. RESULTS: . A mean of 3.3 organs was transplanted when NRP was used compared with 2.6 organs per donor when NRP was not used. When adjusting for organ-specific donor risk profiles, the use of NRP increased the odds of all abdominal organs being transplanted by 3-fold for liver ( P < 0.0001; 95% confidence interval [CI], 2.20-4.29), 1.5-fold for kidney ( P = 0.12; 95% CI, 0.87-2.58), and 1.6-fold for pancreas ( P = 0.0611; 95% CI, 0.98-2.64). Twelve-mo liver transplant survival was superior for recipients of a cDCD NRP graft with a 51% lower risk-adjusted hazard of transplant failure (HR = 0.494). In risk-adjusted analyses, NRP kidneys had a 35% lower chance of developing delayed graft function than non-NRP kidneys (odds ratio, 0.65; 95% CI, 0.465-0.901)' and the expected 12-mo estimated glomerular filtration rate was 6.3 mL/min/1.73 m 2 better if abdominal NRP was used ( P < 0.0001). CONCLUSIONS: . The use of NRP during DCD organ recovery leads to increased organ utilization and improved transplant outcomes compared with conventional organ recovery.

Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure.

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC+ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC+ cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC+ cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP+ airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Post-endotoxin exposure-induced lung inflammation and resolution consequences beneficially impacted by lung-delivered IL-10 therapy.

Although lung diseases typically result from long-term exposures, even a robust, one-time exposure can result in long-lasting consequences. Endotoxin is a ubiquitous environmental/occupational inflammatory agent often used to model airway inflammation. Using a murine model, the return to lung homeostasis following high dose inhalant lipopolysaccharide (LPS, 10-100 µg) exposure were delineated over 2 weeks. LPS-induced rapid weight loss, release of proinflammatory mediators, and inflammatory cell influx with prolonged persistence of activated macrophages CD11c+CD11b+ and recruited/transitioning CD11cintCD11b+ monocyte-macrophages out to 2 weeks. Next, lung-delivered recombinant (r) interleukin (IL)-10 was intratracheally administered for 3 doses initiated 5 h following LPS (10 µg) exposure for 2 days. IL-10 therapy reduced LPS-induced weight loss and increased blood glucose levels. Whereas there was no difference in LPS-induced bronchoalveolar lavage airway fluid cellular influx, total lung cell infiltrates were reduced (37%) with rIL-10 treatment. Post-LPS exposure treatment with rIL-10 strikingly reduced lavage fluid and lung homogenate levels of tumor necrosis factor-α (88% and 93% reduction, respectively), IL-6 (98% and 94% reduction), CXCL1 (66% and 75% reduction), and CXCL2 (47% and 67% reduction). LPS-induced recruited monocyte-macrophages (CD11cintCD11b+) were reduced (68%) with rIL-10. Correspondingly, LPS-induced lung tissue CCR2+ inflammatory monocyte-macrophage were reduced with rIL-10. There were also reductions in LPS-induced lung neutrophils, lymphocyte subpopulations, collagen content, and vimentin expression. These findings support the importance of studying resolution processes for the development of treatment after unintended environmental/occupational biohazard exposures. Short-term, lung-delivered rIL-10 favorably hastened inflammatory recovery processes following acute, high dose inhalant LPS exposure.

Predicting Early Allograft Function After Normothermic Machine Perfusion.

BACKGROUND: Normothermic ex situ liver perfusion is increasingly used to assess donor livers, but there remains a paucity of evidence regarding criteria upon which to base a viability assessment or criteria predicting early allograft function. METHODS: Perfusate variables from livers undergoing normothermic ex situ liver perfusion were analyzed to see which best predicted the Model for Early Allograft Function score. RESULTS: One hundred fifty-four of 203 perfused livers were transplanted following our previously defined criteria. These comprised 84/123 donation after circulatory death livers and 70/80 donation after brain death livers. Multivariable analysis suggested that 2-h alanine transaminase, 2-h lactate, 11 to 29 mmol supplementary bicarbonate in the first 4 h, and peak bile pH were associated with early allograft function as defined by the Model for Early Allograft Function score. Nonanastomotic biliary strictures occurred in 11% of transplants, predominantly affected first- and second-order ducts, despite selection based on bile glucose and pH. CONCLUSIONS: This work confirms the importance of perfusate alanine transaminase and lactate at 2-h, as well as the amount of supplementary bicarbonate required to keep the perfusate pH > 7.2, in the assessment of livers undergoing perfusion. It cautions against the use of lactate as a sole indicator of viability and also suggests a role for cholangiocyte function markers in predicting early allograft function.

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice.

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4+ and CD8+ T cells as well as CD19+CD11b+ autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice.

Liver Transplantation Outcomes From Controlled Circulatory Death Donors: SCS vs in situ NRP vs ex situ NMP.

OBJECTIVE: To compare the outcomes of livers donated after circulatory death (DCD) and undergoing either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion (NMP) with livers undergoing static cold storage (SCS). SUMMARY OF BACKGROUND DATA: DCD livers are associated with increased risk of primary nonfunction, poor function, and nonanastomotic strictures (NAS), leading to underutilization. METHODS: A single center, retrospective analysis of prospectively collected data on 233 DCD liver transplants performed using SCS, NRP, or NMP between January 2013 and October 2020. RESULTS: Ninety-seven SCS, 69 NRP, and 67 NMP DCD liver transplants were performed, with 6-month and 3-year transplant survival (graft survival non-censored for death) rates of 87%, 94%, 90%, and 76%, 90%, and 76%, respectively. NRP livers had a lower 6-month risk-adjusted Cox proportional hazard for transplant failure compared to SCS (hazard ratio 0.30, 95% Confidence Interval 0.08-1.05, P = 0.06). NRP and NMP livers had a risk-adjusted estimated reduction in the mean model for early allograft function score of 1.52 (P < 0.0001) and 1.19 (P < 0.001) respectively compared to SCS. Acute kidney injury was more common with SCS (55% vs 39% NRP vs 40% NMP; P = 0.08), with a lower risk-adjusted peak-to-baseline creatinine ratio in the NRP (P = 0.02). No NRP liver had clinically significant NAS in contrast to SCS (14%) and NMP (11%, P = 0.009), with lower risk-adjusted odds of overall NAS development compared to SCS (odds ratio = 0.2, 95%CI 0.06-0.72, P = 0.01). CONCLUSION: NRP and NMP were associated with better early liver function compared to SCS, whereas NRP was associated with superior preservation of the biliary system.

Interleukin (IL)-33 immunobiology in asthma and airway inflammatory diseases.

OBJECTIVE: Identify key features of IL-33 immunobiology important in allergic and nonallergic airway inflammatory diseases and potential therapeutic strategies to reduce disease burden. DATA SOURCES: PubMed, clinicaltrials.gov. STUDY SELECTIONS: A systematic and focused literature search was conducted of PubMed from March 2021 to December 2021 using keywords to either PubMed or BioMed Explorer including IL-33/ST2, genetic polymorphisms, transcription, translation, post-translation modification, nuclear protein, allergy, asthma, and lung disease. Clinical trial information on IL-33 was extracted from clinicaltrials.gov in August 2021. RESULTS: In total, 72 publications with relevance to IL-33 immunobiology and/or clinical lung disease were identified (allergic airway inflammation/allergic asthma n = 26, non-allergic airway inflammation n = 9, COPD n = 8, lung fibrosis n = 10). IL-33 levels were higher in serum, BALF and/or lungs across inflammatory lung diseases. Eight studies described viral infections and IL-33 and 4 studies related to COVID-19. Mechanistic studies (n = 39) including transcript variants and post-translational modifications related to the immunobiology of IL-33. Single nucleotide polymorphism in IL-33 or ST2 were described in 9 studies (asthma n = 5, inflammatory bowel disease n = 1, mycosis fungoides n = 1, ankylosing spondylitis n = 1, coronary artery disease n = 1). Clinicaltrials.gov search yielded 84 studies of which 17 were related to therapeutic or biomarker relevance in lung disease. CONCLUSION: An integral role of IL-33 in the pathogenesis of allergic and nonallergic airway inflammatory disease is evident with several emerging clinical trials investigating therapeutic approaches. Current data support a critical role of IL-33 in damage signaling, repair and regeneration of lungs.