CELA1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency

Devine, Andrew J.; Smith, Noah J.; Joshi, Rashika; Fan, Qiang; Borchers, Michael T.; Clair, Gérémy; Adkins, Joshua N.; Varisco, Brian M.

doi:10.21203/rs.3.rs-2617812/v1

Cited by 2 publications

(4 citation statements)

References 29 publications

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“…Our findings are most consistent with our previously described model that CELA1 acts in the progression but not the initiation of emphysema (8). This would explain seemingly contradictory findings that Cela1 -/and KF4-treated mice develop less emphysema in response to 6 months of cigarette smoke exposure compared to wild-type or IgG-treated mice, (8) but cigarette smoke-exposed AAT -/-&Cela1 -/mice have slightly but significantly greater emphysema than AAT -/mice (7). Daily cigarette smoke exposure causes persistent inflammation and the activity of leukocyte-associated proteases like neutrophil elastase, cathepsin G, and matrix metalloproteinases are likely greater in this model than in the PPE model used in this study.…”

Section: Discussionsupporting

confidence: 90%

“…Of course, the dose at which injury was observed was 10-fold higher than the therapeutic dose, and it may be that KF4 is effective at even lower doses. The model of AAT-deficient emphysema used was previously shown to be progressive (7), but it is a post-injury model and lacks the clinical relevance that other models like cigarette smoke exposure have. Lastly, the combination of KF4 and AAT replacement could have caused some amount of injury associated with a higher osmotic load obscuring potential benefit of combination therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Using the previously described low-dose PPE model of AAT-deficient emphysema (7), we performed a dose titration experiment using lung homogenate from AAT -/mice administered 0.2 units of tracheal PPE and treated with IgG 2 mg/kg, KF4 2 mg/kg or KF4 0.5 mg/kg in a colorimetric elastase activity assay. Both KF4 doses significantly reduced lung elastase activity (Figure 4A).…”

Section: Efficacy Of Kf4 In Preventing Emphysemamentioning

confidence: 99%

“…AAT is an anti-protease that neutralizes Neutrophil Elastase, Cathepsin G, and Proteinase-3 (4,5). Our group has shown that AAT also neutralizes and an alveolar type 2 cell-secreted serine protease called Chymotrypsin-like Elastase 1 (CELA1) (6)(7)(8). CELA1 plays a physiologic role in the postnatal lung by reducing lung elastase (6) and at baseline Cela1 -/mice have slightly smaller alveoli than wild type mice.…”

Section: Introductionmentioning

confidence: 99%

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KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency

Devine,

Smith,

Joshi

et al. 2024

Preprint

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Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like Elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression. Cela1-deficiency is protective in a murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in PPE and cigarette smoke models in wild type mice. We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lung, pancreas, small intestine, and spleen. In toxicity studies, mice treated with KF4 25 mg/kg weekly for four weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose IgG. In histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25 mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5 mg/kg reduced the lung elastase activity of AAT-/- mice treated with 0.2 units of PPE. In this injury model, AAT-/- mice treated with KF4 1 mg/kg weekly, human purified AAT 60 mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1 mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 & AAT was similar. While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Efficacy Of Kf4 In Preventing Emphysemamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency

Devine,

Smith,

Joshi

et al. 2024

Preprint

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A titratable murine model of progressive emphysema using tracheal porcine pancreatic elastase

Joshi,

Devine,

Joshi

et al. 2023

Sci Rep

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Progressive emphysema often leads to end-stage lung disease. Most mouse models of emphysema are typically modest (i.e. cigarette smoke exposure), and changes over time are difficult to quantify. The tracheal porcine pancreatic elastase model (PPE) produces severe injury, but the literature is conflicted as to whether emphysema improves, is stable, or progresses over time. We hypothesized a threshold of injury below which repair would occur and above which emphysema would be stable or progress. We treated 8-week-old C57BL6 mixed sex mice with 0, 0.5, 2, or 4 activity units of PPE in 100 µL PBS and performed lung stereology at 21 and 84 days. There were no significant differences in weight gain or mouse health. Despite minimal emphysema at 21-days in the 0.5 units group (2.8 µm increased mean linear intercept, MLI), MLI increased by 4.6 µm between days 21 and 84 (p = 0.0007). In addition to larger MLI at 21 days in 2- and 4-unit groups, MLI increases from day 21 to 84 were 17.2 and 34 µm respectively (p = 0.002 and p = 0.0001). Total lung volume increased, and alveolar surface area decreased with time and injury severity. Contrary to our hypothesis, we found no evidence of alveolar repair over time. Airspace destruction was both progressive and accelerative. Future mechanistic studies in lung immunity, mechano-biology, senescence, and cell-specific changes may lead to novel therapies to slow or halt progressive emphysema in humans.

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CELA1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency

Cited by 2 publications

References 29 publications

KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency

KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency

A titratable murine model of progressive emphysema using tracheal porcine pancreatic elastase

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