| 1. |
- Baluk, Peter, et al.
(author)
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Transgenic Overexpression of Interleukin-1β Induces Persistent Lymphangiogenesis But Not Angiogenesis in Mouse Airways.
- 2013
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In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 182:4, s. 1434-1447
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Journal article (peer-reviewed)abstract
- These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1β mice that conditionally overexpress IL-1β in Clara cells to determine whether IL-1β can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1β production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1β, and lymphotoxin-β), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1β overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1β induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba-immunoreactive macrophages. Because neutrophils contribute to IL-1β-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1β/CXCR2(-/-) mice had the usual IL-1β-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1β, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1β overexpression in mouse airways is driven by VEGF-C/D from macrophages but notneutrophils recruited by chemokines from epithelial cells that express IL1R1.
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| 2. |
- Bry, Kristina, 1953, et al.
(author)
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Mechanisms of inflammatory lung injury in the neonate: lessons from a transgenic mouse model of bronchopulmonary dysplasia.
- 2010
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In: Seminars in perinatology. - : Elsevier BV. - 1558-075X .- 0146-0005. ; 34:3, s. 211-21
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Research review (peer-reviewed)abstract
- The role of inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. By using a transgenic mouse expressing the inflammatory cytokine interleukin (IL)-1beta in the lung, we have shown that perinatal expression of IL-1beta causes a BPD-like illness in infant mice. We have used this model to identify mechanisms by which inflammation causes neonatal lung injury. Increased matrix metalloproteinase (MMP)-9 activity is associated with BPD. MMP-9 deficiency worsens alveolar hypoplasia in IL-1beta-expressing newborn mice, suggesting that MMP-9 has a protective role in neonatal inflammatory lung injury. The beta6 integrin subunit, an activator of transforming growth factor-beta, is involved in adult lung disease. Absence of the beta6 integrin subunit improves alveolar development in IL-1beta-expressing mice, suggesting that the beta6 integrin subunit is a pathogenetic factor in inflammatory lung disease in the newborn. The authors of clinical studies who have examined maternal inflammation as a risk factor for BPD have found variable results. We have shown that maternal IL-1beta production preceding fetal IL-1beta production prevents lung inflammation, alveolar hypoplasia, and airway remodeling in newborn IL-1beta-expressing mice. Thus, maternal inflammation may protect the newborn lung against subsequent inflammatory injury. In contrast, when maternal and fetal production of IL-1beta are induced simultaneously, the development of IL-1beta-induced lung disease in the newborn is not prevented.
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| 3. |
- Bry, Maija, et al.
(author)
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Insulin-like growth factor-I (IGF-I) aggravates lung injury in a mouse model of bronchopulmonary dysplasia
- 2015
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In: Pediatric Academic Societies Annual Meeting.
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Conference paper (other academic/artistic)abstract
- Background: Trials using continuous intravenous administration of insulin-like growth factor (IGF)-I to preterm infants for the prevention of retinopathy of prematurity (ROP) are currently underway (Ley et al., 2013). However, the effects of exogenous IGF-I on developing organs of the newborn are unknown. IGF-I has been shown to play a critical role in the pathogenesis of asthma (Lee et al., 2014). In addition, IGF-I levels are high in the lungs of infants with bronchopulmonary dysplasia (BPD) (Capoluongo et al., 2008). We have previously shown that perinatal pulmonary IL-1b expression causes a BPD-like lung disease in newborn mice. Objective: To study the effects of systemic postnatal administration of IGF-I on lung inflammation and morphogenesis in a murine model of BPD. Methods: IL-1b production in pulmonary epithelium of transgenic fetuses and pups was induced by doxycycline administration (0.5 mg/ml) in drinking water to pregnant and lactating dams from the beginning of pregnancy until sacrifice of the pups on postnatal day (PN) 7. Three intraperitoneal injections of recombinant human IGF-I (1 μg/g body weight) or an equal volume of PBS were administered to transgenic IL-1β-expressing mice and their littermate controls on PN 2, 4 and 6. Lung inflammation and structure were studied on PN 7. Results: IGF-I significantly increased both neutrophil and macrophage infiltration in the lungs of IL-1b-expressing infant mice, and also significantly increased the number of neutrophils in the lungs of littermate controls not expressing IL-1β. In addition, IGF-I increased alveolar septal wall thickness in IL-1b-expressing mice, indicating that IGF-I potentiated IL-1b-induced lung injury. Conclusions: IGF-I aggravated lung inflammation and injury in the newborn lung, indicating that IGF-I administration may have deleterious effects on lung development in preterm infants at risk of BPD.
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| 4. |
- Bäckström, Erica, 1980, et al.
(author)
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Developmental Stage is a Major Determinant of Lung Injury in a Murine Model of Bronchopulmonary Dysplasia.
- 2011
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In: Pediatric research. - 1530-0447. ; 69:4, s. 312-318
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Journal article (peer-reviewed)abstract
- Bronchopulmonary dysplasia (BPD) is a common inflammatory lung disease in premature infants. To study the hypothesis that the sensitivity of the lung to inflammatory injury depends on the developmental stage, we studied postnatal lung development in transgenic mice expressing human interleukin-1β (hIL-1β) in the lungs during the late canalicular-early saccular, saccular, or late saccular-alveolar stage. Overexpression of hIL-1β in the saccular stage caused arrest in alveolar development, airway remodeling, and goblet cell hyperplasia in the lungs as well as poor growth and survival of infant mice. Overexpression of hIL-1β during the late canalicular-early saccular stage did not adversely affect lung development, growth, or survival of the pups. Mice expressing hIL-1β from the late saccular to alveolar stage had smaller alveolar chord length, thinner septal walls, less airway remodeling and mucus metaplasia, and better survival than mice expressing hIL-1β during the saccular stage. Human IL-1β overexpression in the saccular stage was sufficient to cause a BPD-like illness in infant mice, whereas the lung was more resistant to hIL-1β-induced injury at earlier and later developmental stages. ABBREVIATIONS:
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| 5. |
- Hogmalm, Anna, 1981, et al.
(author)
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beta6 Integrin subunit deficiency alleviates lung injury in a mouse model of bronchopulmonary dysplasia.
- 2010
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In: American journal of respiratory cell and molecular biology. - 1535-4989. ; 43:1, s. 88-98
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Journal article (peer-reviewed)abstract
- Pulmonary inflammation is associated with the development of bronchopulmonary dysplasia in premature infants. We have previously shown that perinatal pulmonary expression of human IL-1beta is sufficient to cause a lung disease similar to bronchopulmonary dysplasia, characterized by inflammation, impaired alveolarization, poor postnatal growth, and increased mortality in infant mice. The alphavbeta6 integrin plays a critical role in regulating inflammation in the adult lung. To study the role of the beta6 integrin subunit in neonatal inflammatory lung disease, we compared the pulmonary development in IL-1beta-expressing infant mice with wild-type or null beta6 integrin loci. Absence of the beta6 integrin subunit decreased the mortality and improved the postnatal growth of IL-1beta-expressing pups. The disrupted alveolar development of IL-1beta-expressing mice was improved by beta6 integrin deficiency. IL-1beta-expressing beta6(-/-) pups had shorter alveolar chord length and thinner alveolar walls than IL-1beta-expressing beta6(+/+) pups. In addition, the absence of the beta6 integrin subunit reduced IL-1beta-induced neutrophil and macrophage infiltration into the alveolar spaces. beta6 integrin subunit deficiency suppressed inflammation and goblet cell hyperplasia in the airways and alleviated airway remodeling in IL-1beta-expressing mice. The expression of the chemoattractant proteins, keratinocyte-derived chemokine, macrophage-inflammatory protein-2, calgranulin A, and calgranulin B, of osteopontin, and of the chitinase-like lectins, Ym1 and Ym2, was lower in IL-1beta-expressing beta6(-/-) than in IL-1beta-expressing beta6(+/+) mice. We conclude that absence of the beta6 integrin subunit protects the infant murine lung against IL-1beta-induced inflammation and injury.
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| 6. |
- Hogmalm, Anna, 1981, et al.
(author)
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IL-1β expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice.
- 2014
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In: American journal of physiology. Lung cellular and molecular physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 306:1
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Journal article (peer-reviewed)abstract
- Perinatal inflammation and the inflammatory cytokine IL-1 can modify lung morphogenesis. To examine the effects of antenatal expression of IL-1β in the distal airway epithelium on fetal lung morphogenesis, we studied lung development and surfactant expression in fetal mice expressing human IL-1β under the control of the surfactant protein (SP)-C promoter. IL-1β-expressing pups suffered respiratory failure and died shortly after birth. IL-1β caused fetal lung inflammation and enhanced the expression of keratinocyte-derived chemokine (KC/CXCL1) and monocyte chemoattractant protein 3 (MCP-3/CCL7), the calgranulins S100A8 and S100A9, the acute-phase protein serum amyloid A3 (SAA3), the chitinase-like proteins Ym1 and Ym2, and pendrin. IL-1β decreased the percentage of the total distal lung area made up of air saccules and the number of air saccules in the lungs of fetal mice. IL-1β inhibited the expression of VEGF-A and of its receptors VEGFR-1 and VEGFR-2. The percentage of the cellular area of the distal lung made up of capillaries was decreased in IL-1β-expressing fetal mice. IL-1β suppressed the production of SP-B and pro-SP-C, and decreased the amount of phosphatidylcholine and the percentage of palmitic acid in the phosphatidylcholine fraction of lung phospholipids, indicating that IL-1β prevented the differentiation of type II epithelial cells. The production of Clara cell secretory protein (CCSP) in the nonciliated bronchiolar (Clara) cells was likewise suppressed by IL-1β. In conclusion, expression of IL-1β in the epithelium of the distal airways disrupted the development of the airspaces and capillaries in the fetal lung and caused fatal respiratory failure at birth.
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| 7. |
- Hogmalm, Anna, 1981
(author)
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Mechanisms of Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects preterm infants. Increased levels of inflammatory mediators in the amniotic fluid and in the lungs of preterm infants are associated with the development of BPD. It has been shown that infant transgenic mice that express interleukin (IL)-1β in the lung epithelium from approximately embryonal day 14 (pseudoglandular stage of lung development) develop a pulmonary injury that resembles BPD, supporting the idea that inflammation plays an important role in the pathogenesis of BPD. The mechanisms by which inflammation causes lung injury have not been identified. The aim of this thesis was to define mechanisms by which perinatal inflammatory lung injury develops by using transgenic mice that express IL-1β in the lung epithelium in an inducible manner. The β6 integrin subunit has previously been shown to be involved in the progression of pulmonary diseases in adult mice. To investigate the involvement of the β6 integrin subunit in IL-1β-induced lung disease in the neonate, lung development of IL-1β-expressing mice lacking the β6 integrin subunit were compared with that of IL-1β-expressing mice with wild-type β6 loci. Absence of the β6 integrin subunit alleviated the IL-1β-induced lung injury, as demonstrated by smaller alveoli, thinner alveolar walls, and a milder lung inflammation than IL-1β-expressing mice with wild-type β6 integrin loci. The results suggest that the β6 integrin subunit plays a role in the development of neonatal lung disease. Increased levels of matrix metalloproteinase (MMP)-9 and an imbalance between proteases and antiproteases in the lungs of infants and animals developing BPD have led to the hypothesis that MMP-9 may be involved in the pathogenesis of the disease. No differences in lung histology were detected between mice with wild-type MMP-9 loci and mice with null MMP-9 loci, implying a non-essential role of MMP-9 during lung development. However, IL-1β caused a more severe alveolar hypoplasia in mice deficient in MMP-9 than in MMP-9 wild-type mice, suggesting that MMP-9 may have a protective role during inflammatory lung injury. A short-term exposure of IL-1 has been shown to accelerate development of the surfactant system in fetal rabbits and lambs. Using transgenic mice where the expression of IL-1β is restricted to the distal lung epithelium, the effects on lung development and function of chronic prenatal IL-1β production were studied. Distal lung expression of IL-1β disrupted acinar bud formation prior to birth and decreased the expression of the important surfactant proteins SP-B and SP-C. The 100% mortality observed among the IL-1β-expressing mice was probably due to the inflammation-induced structural changes and to deficient surfactant function. The results suggest that an early and continuous inflammatory stimulus in the distal lung epithelium causes severe lung injury and disrupts surfactant production.
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| 8. |
- Hogmalm, Anna, 1981, et al.
(author)
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Postnatal lung inflammation leads to abnormal lung structure and function in adulthood
- 2015
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In: Pediatric Academic Societies Annual Meeting.
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Conference paper (other academic/artistic)abstract
- Background: Exposure to chorioamnionitis, mechanical ventilation, and the use of oxygen therapy cause inflammation in the preterm lung. The long-term consequences of neonatal pulmonary inflammation on lung structure and function have been incompletely characterized. We have previously shown that postnatal pulmonary IL-1b expression during the late saccular to alveolar stage of lung development causes lung inflammation and a mild increase in alveolar size and septal wall thickness in infant mice. Objective: To study the consequences of postnatal IL-1b expression in the newborn lung on lung structure and function in adulthood. Methods: To induce IL-1b production in the pulmonary epithelium of transgenic mice during the late saccular to alveolar stage of lung development, doxycycline (0.15 mg) was administered via intraperitoneal injections to transgenic pups and their littermate controls on postnatal days (PN) 0, 0.5, and 1. Lung inflammation, structure and airway reactivity (assessed by flexiVentTM at methacholine concentrations 0-200 mg/ml) were studied on PN 21 and 42. Results: IL-1b expression in the infant mice caused lack of alveolar septation in the lungs of young (PN 21) and adult (PN 42) mice (Fig. 2) and increased airway reactivity in the mice (Fig. 3). Conclusions: Postnatal lung inflammation in newborn mice caused abnormal lung structure and function in adulthood. Lack of alveolar septation in the newborn persisted after IL-1b production was stopped. Neonatal pulmonary inflammation thus has long-term consequences on the lung and may cause respiratory impairment in adulthood.
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| 9. |
- Hogmalm, Anna, 1981, et al.
(author)
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Pulmonary IL-1β expression in early life causes permanent changes in lung structure and function in adulthood.
- 2018
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In: American journal of physiology. Lung cellular and molecular physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 314:6, s. 936-945
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Journal article (peer-reviewed)abstract
- Chorioamnionitis, mechanical ventilation, oxygen therapy, and postnatal infection promote inflammation in the newborn lung. The long-term consequences of pulmonary inflammation during infancy have not been well characterized. The aim of this study was to examine the impact of inflammation during the late saccular to alveolar stages of lung development on lung structure and function in adulthood. To induce IL-1β expression in the pulmonary epithelium of mice with a tetracycline-inducible human IL-1β transgene, doxycycline was administered via intraperitoneal injections to bitransgenic pups and their littermate controls on postnatal days (PN) 0, 0.5, and 1. Lung structure, inflammation, and airway reactivity were studied in adulthood. IL-1β production in early life resulted in increased numbers of macrophages and neutrophils on PN21, but inflammation subsided by PN42. Permanent changes in alveolar structure, i. e. larger alveoli and thicker alveolar walls, were present from PN21 to PN84. Lack of alveolar septation thus persisted after IL-1β production and inflammation had ceased. Early IL-1β production caused goblet cell hyperplasia, enhanced calcium-activated chloride channel 3 (CLCA3) protein expression, and increased airway reactivity in response to methacholine on PN42. Lymphoid follicles were present adjacent to small airways in the lungs of adult bitransgenic mice, and levels of the B-cell chemoattractant CXC-motif ligand (CXCL) 13 were elevated in the lungs of bitransgenic mice compared to controls. In conclusion, IL-1β-induced pulmonary inflammation in early life causes a chronic lung disease in adulthood.
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| 10. |
- Hogmalm, Anna, 1981, et al.
(author)
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Role of CXC Chemokine Receptor-2 in a Murine Model of Bronchopulmonary Dysplasia.
- 2012
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In: American journal of respiratory cell and molecular biology. - 1535-4989. ; 47:6, s. 746-758
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Journal article (peer-reviewed)abstract
- The contribution of neutrophils and CXC chemokines to the pathogenesis of bronchopulmonary dysplasia (BPD) is not well defined. Transgenic expression of interleukin (IL)-1β in the pulmonary epithelium causes lung inflammation and disrupts alveolar development in infant mice. To study the hypothesis that CXC chemokine receptor 2 (CXCR2) is a mediator of inflammatory lung injury, we compared lung development in IL-1β-expressing mice with wild-type (IL-1β/CXCR2+/+) or null (IL-1β/CXCR2-/-) CXCR2 loci. CXCR2 deficiency abolished the transmigration of neutrophils into the alveolar lumen in IL-1β-expressing mice but did not alter the number of neutrophils in the parenchyma. Deletion of CXCR2 increased the alveolar chord length and reduced the survival of the mice when IL-1β was expressed from the pseudoglandular to the alveolar stages. The capillary configuration was highly abnormal, in both IL-1β/CXCR2+/+ and IL-1β/CXCR2-/- lungs, but in very different ways. The cellular area of the parenchyma and the total capillary area of IL-1β/CXCR2+/+ and IL-1β/CXCR2-/- were smaller than those of control/CXCR2+/+ and control/CXCR2-/- mice, but the ratio of capillary area to cellular area was similar in all four genotypes. When IL-1β was expressed during the saccular stage, IL-1β/CXCR2-/- mice had smaller alveolar chord length and better survival than IL-1β/CXCR2+/+ mice. Independent of the timing of IL-1β expression, IL-1β increased alveolar septal thickness in mice with wild-type CXCR2 loci but not in CXCR2 null mice. Depending on the developmental stage at the time of the inflammatory insult, inhibition of the CXCR2-pathway may have opposite effects on alveolar septation in the neonatal lung.
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| 11. |
- Lukkarinen, Heikki, et al.
(author)
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Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia.
- 2009
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In: American journal of respiratory cell and molecular biology. - 1535-4989. ; 41:1, s. 59-68
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Journal article (peer-reviewed)abstract
- Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 beta (IL-1 beta) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1 beta-induced lung injury in the newborn, we compared the effects of IL-1 beta on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 beta with wild-type (IL-1 beta/MMP-9(+/+)) or null (IL-1 beta/MMP-9(-/-)) MMP-9 loci. IL-1 beta increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9(+/+) mice. IL-1 beta/MMP-9(-/-) mice had fewer neutrophils but more macrophages in the lungs than did IL-1 beta/MMP-9(+/+) mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1 beta-expressing mice. IL-1 beta/MMP-9(-/-) mice had more severe alveolar hypoplasia than IL-1 beta/MMP-9(+/+) mice, implying that IL-1 beta-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.
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