Need and benefit of communication training for NICU nurses.

Objectives: To assess the effects of a new communication course for neonatal intensive care unit (NICU) nurses on nurses' confidence in communicating with families, and to explore communication-related issues experienced by the nurses and their relationship to burnout. Study design: Twenty-nine nurses participated in an interactive course based on communication cases from the NICU. Participants' experience of communication with parents was assessed. They completed the Maslach Burnout Inventory. Self-reported communication skills were assessed before and after the course and at four-month follow-up. Results: Only one nurse reported previous nursing-related communication training. High burnout scores were associated with communication-related difficulties, especially lack of time for communication. The course improved participants' confidence in their communication skills in challenging situations, including those where parents express distress or ask questions the nurse cannot answer. Participants found the course highly interesting, useful and necessary for their work. Conclusion: Interactive, learner-centered training addressing issues specific to communication at the NICU was effective and highly appreciated. Innovation: The course centered on a unique variety of reality-based communication cases from the NICU, relevant to the nurses' work and stimulating their reflection. An innovative feature was the emphasis on nurses' perspective and the importance of communication for their coping.

IL-1ß dysregulates cGMP signaling in the newborn lung.

Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1ß regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1ß were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1ß treatment did not alter sGCα1 mRNA stability, although it reduced sGCα1 promoter activity. Transforming growth factor-ß (TGFß)-activated kinase-1 (TAK1) was determined to be required for IL-1ß's regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1ß-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-κB (NF-κB) signaling played a critical role in the IL-1ß-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-κB subunit (RelA) binding to the sGCα1 promoter after IL-1ß treatment unless treated with an IκB kinase-2 inhibitor. Also, this NF-κB signaling inhibition protected sGCα1 expression in IL-1ß-treated fibroblasts. Lastly, using transgenic mice in which active IL-1ß was conditionally expressed in lung epithelial cells, we established that IL-1ß expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1ß inhibits cGMP signaling in the newborn lung.

SITUPS: a new tool for oral case presentation in the paediatric emergency department.

AIM: We developed a new case presentation technique, SITUPS, and studied its impact on the patient presentations by medical students at a paediatric emergency department. The students' opinions about the usefulness of the technique were also assessed. METHODS: The students saw patients both before and after introduction to SITUPS. Their presentations were analysed by the clinical instructor using a student assessment form. The students filled in a 15-item questionnaire about their opinion of SITUPS as a learning tool. RESULTS: Twenty-eight students were evaluated both without and with SITUPS in a total of 78 presentations. Using SITUPS, the students gave more complete case presentations without increasing the presentation time. The main areas of improvement were discussing differential diagnoses, proposing a management plan, and identifying where they lacked knowledge and needed to ask the instructor questions. The students found SITUPS particularly helpful in identifying family and social issues of significance, thinking of relevant questions to ask the patient and the family, and thinking through differential diagnoses. CONCLUSION: We propose a new case presentation technique, SITUPS, for use at the paediatric emergency department. With the help of SITUPS, the medical students gave more complete case presentations in a time-effective manner.

Pulmonary IL-1ß expression in early life causes permanent changes in lung structure and function in adulthood.

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-1ß expression in the pulmonary epithelium of mice with a tetracycline-inducible human IL-1ß 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-1ß 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-1ß production and inflammation had ceased. Early IL-1ß 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 with controls. In conclusion, IL-1ß-induced pulmonary inflammation in early life causes a chronic lung disease in adulthood.

Using telemedicine in the care of newborn infants after discharge from a neonatal intensive care unit reduced the need of hospital visits.

AIM: This study examined the use of telemedicine as a means to follow up infants discharged from a Swedish neonatal intensive care unit to home health care. METHODS: Families were randomised to either a control group receiving standard home health care (n = 42 families) or a telemedicine group receiving home health care with telemedicine support (n = 47 families) after discharge from the hospital. Both groups had follow-up hospital appointments with the neonatal nurse. In the telemedicine group, appointments were supplemented by the use of a specially designed web page and video calls. RESULTS: The use of the web page and video calls decreased the number of emergency visits to the hospital (p = 0.047). In the telemedicine group, 26% of the families felt they had more scheduled appointments than necessary, whereas only 6% of the families in the control group thought so (p = 0.037). The parents were highly satisfied with the use of telemedicine. Although the nurses were favourable to using telemedicine, the rigid organisation of the home healthcare programme and the nurses' schedules and work routines prevented its optimal use. CONCLUSION: The use of telemedicine decreased the need of hospital visits. Organisational adaptations would be necessary to make the best use of telemedicine.

Communication skills training enhances nurses' ability to respond with empathy to parents' emotions in a neonatal intensive care unit.

AIM: We quantitatively analysed the effect of a course in communication on the content of nurse-parent encounters and the ability of nurses to respond to the empathic needs of parents in a level III neonatal intensive care unit. METHODS: We evaluated 36 and 45 nurse-parent encounters audio recorded before and after 13 neonatal nurses attended a communication course. The number of empathic opportunities, the nurses' responses to these and the ways they involved parents in their infants' care were studied. RESULTS: Both before and after the course, the nurses talked more than the parents during the conversations. This nurse-centredness decreased after the course. The use of empathic or exploring responses to empathic opportunities increased from 19.9 ± 9.0% to 53.8 ± 8.9% (p = 0.027), whereas ignoring the feelings of the parents or giving inadequate advice decreased from 63.0 ± 10.0% to 27.5 ± 8.4% (p = 0.043) after the course. Use of statements expressing caring for the parents and encouragement for parents to participate in the care of their infant increased after the course (p = 0.0034 and p = 0.043, respectively). The nurses felt the course was very useful for their profession. CONCLUSION: A course in communication techniques improved nurses' ability to respond to parents' feelings with empathy.

Parents' experiences of communication with neonatal intensive-care unit staff: an interview study.

BACKGROUND: An infant's admission to a neonatal intensive-care unit (NICU) inevitably causes the parents emotional stress. Communication between parents and NICU staff is an essential part of the support offered to the parents and can reduce their emotional stress. The aim of this study was to describe parents' experiences of communication with NICU staff. METHODS: A hermeneutic lifeworld interview study was performed with 18 families whose children were treated in the level III NICU at a university hospital in Sweden. The interviews were analysed to gain an interpretation of the phenomenon of how parents in the NICU experienced their communication with the staff, in order to find new ways to understand their experience. RESULTS: Parents' experience of communication with the staff during their infant's stay at the NICU can be described by the main theme 'being given attention or ignored in their emotional situation'. The main theme derives from three themes; (1) meeting a fellow human being, (2) being included or excluded as a parent and (3) bearing unwanted responsibility. CONCLUSIONS: This study shows that parents experienced communication with the NICU staff as essential to their management of their situation. Attentive communication gives the parents relief in their trying circumstances. In contrast, lack of communication contributes to feelings of loneliness, abandonment and unwanted responsibility, which adds to the burden of an already difficult situation. The level of communication in meetings with staff can have a decisive influence on parents' experiences of the NICU. The staff should thus be reminded of their unique position to help parents handle their emotional difficulties. The organization should facilitate opportunities for good communication between parents and staff through training, staffing and the physical health care environment.

IL-1ß expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice.

Perinatal inflammation and the inflammatory cytokine IL-1 can modify lung morphogenesis. To examine the effects of antenatal expression of IL-1ß in the distal airway epithelium on fetal lung morphogenesis, we studied lung development and surfactant expression in fetal mice expressing human IL-1ß under the control of the surfactant protein (SP)-C promoter. IL-1ß-expressing pups suffered respiratory failure and died shortly after birth. IL-1ß 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, the chitinase-like proteins Ym1 and Ym2, and pendrin. IL-1ß 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-1ß inhibited the expression of VEGF-A and 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-1ß-expressing fetal mice. IL-1ß 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-1ß prevented the differentiation of type II epithelial cells. The production of Clara cell secretory protein in the nonciliated bronchiolar (Clara) cells was likewise suppressed by IL-1ß. In conclusion, expression of IL-1ß 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.

Strengths and weaknesses of parent-staff communication in the NICU: a survey assessment.

BACKGROUND: Parents of infants hospitalized in the neonatal intensive care unit (NICU) find themselves in a situation of emotional strain. Communication in the NICU presents special challenges due to parental stress and the complexity of the highly technologized environment. Parents' need for communication may not always be met by the NICU staff. This study aimed to describe strengths and weaknesses of parent-nurse and parent-doctor communication in a large level III NICU in Sweden in order to improve our understanding of parents' communication needs. METHODS: Parents were asked to complete a survey consisting of sixteen questions about their experiences of communication with nurses and doctors in the NICU. In each question the parents evaluated some aspect of communication on a five- or six-point Likert scale. They also had the opportunity on each question to comment on their experiences in their own words. Data were analyzed using IBM SPSS Statistics 20.0 and qualitative manifest content analysis. RESULTS: 270 parents (71.4%) completed the survey. Parents generally rated communication with the staff in the NICU positively and appreciated having received emotional support and regular information about their child´s care. Although a large majority of the parents were satisfied with their communication with doctors and nurses, only about half of the parents felt the nurses and doctors understood their emotional situation very well. Some parents would have desired easier access to conversations with doctors and wanted medical information to be given directly by doctors rather than by nurses. Parents' communication with the staff was hampered when many different nurses were involved in caring for the infant or when the transfer of information in connection with shift changes or between the maternity ward and NICU was poor. Parents also desired to be present during doctors' rounds on their infant. CONCLUSIONS: Training both doctors and nurses in communication skills, especially in how to meet parents' emotional needs better, could make communication at the NICU more effective and improve parental well-being. Creating a framework for the parents of what to expect from NICU communication might also be helpful. In addition, our results support the use of primary nurse teams to improve continuity of care and thereby promote successful communication.

A randomized controlled study about the use of eHealth in the home health care of premature infants.

BACKGROUND: One area where the use of information and communication technology (ICT), or eHealth, could be developed is the home health care of premature infants. The aim of this randomized controlled study was to investigate whether the use of video conferencing or a web application improves parents' satisfaction in taking care of a premature infant at home and decreases the need of home visits. In addition, nurses' attitudes regarding the use of these tools were examined. METHOD: Thirty-four families were randomized to one of three groups before their premature infant was discharged from the hospital to home health care: a control group receiving standard home health care (13 families); a web group receiving home health care supplemented with the use of a web application (12 families); a video group with home health care supplemented with video conferencing using Skype (9 families). Families and nursing staff answered questionnaires about the usefulness of ICT. In addition, semi-structured interviews were conducted with 16 families. RESULTS: All the parents in the web group found the web application easy to use. 83% of the families thought it was good to have access to their child's data through the application. All the families in the video group found Skype easy to use and were satisfied with the video calls. 88% of the families thought that video calls were better than ordinary phone calls. 33% of the families in the web group and 75% of those in the video group thought the need for home visits was decreased by the web application or Skype. 50% of the families in the web group and 100% of those in the video group thought the web application or the video calls had helped them feel more confident in caring for their child. Most of the nurses were motivated to use ICT but some were reluctant and avoided using the web application and video conferencing. CONCLUSION: The families were satisfied with both the web application and video conferencing. The families readily embraced the use of ICT, whereas motivating some of the nurses to accept and use ICT was a major challenge.

Transgenic overexpression of interleukin-1ß induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1ß mice that conditionally overexpress IL-1ß in Clara cells to determine whether IL-1ß can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1ß 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-1ß, and lymphotoxin-ß), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1ß overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1ß 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/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1ß-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1ß/CXCR2(-/-) mice had the usual IL-1ß-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-1ß, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1ß overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.

Role of CXC chemokine receptor-2 in a murine model of bronchopulmonary dysplasia.

The contribution of neutrophils and CXC chemokines to the pathogenesis of bronchopulmonary dysplasia is not well defined. The transgenic expression of IL-1ß 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-1ß-expressing mice with wild-type (IL-1ß/CXCR2(+/+)) or null (IL-1ß/CXCR2(-/-)) CXCR2 loci. CXCR2 deficiency abolished the transmigration of neutrophils into the alveolar lumen in IL-1ß-expressing mice, but did not alter the number of neutrophils in the parenchyma. The deletion of CXCR2 increased the alveolar chord length and reduced the survival of mice when IL-1ß was expressed from the pseudoglandular to the alveolar stages. The capillary configuration was highly abnormal in both IL-1ß/CXCR2(+/+) and IL-1ß/CXCR2(-/-) lungs, but in very different ways. The cellular area of the parenchyma and the total capillary area of IL-1ß/CXCR2(+/+) and IL-1ß/CXCR2(-/-) mice 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-1ß was expressed during the saccular stage, IL-1ß/CXCR2(-/-) mice had smaller alveolar chord lengths and better survival than did IL-1ß/CXCR2(+/+) mice. Independent of the timing of IL-1ß expression, IL-1ß 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 exert opposite effects on alveolar septation in the neonatal lung.

Developmental stage is a major determinant of lung injury in a murine model of bronchopulmonary dysplasia.

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 IL-1ß (hIL-1ß) in the lungs during the late canalicular-early saccular, saccular, or late saccular-alveolar stage. Overexpression of hIL-1ß 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-1ß during the late canalicular-early saccular stage did not adversely affect lung development, growth, or survival of the pups. Mice expressing hIL-1ß 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-1ß during the saccular stage. Human IL-1ß overexpression in the saccular stage was sufficient to cause a BPD-like illness in infant mice, whereas the lung was more resistant to hIL-1ß-induced injury at earlier and later developmental stages.

Mechanisms of inflammatory lung injury in the neonate: lessons from a transgenic mouse model of bronchopulmonary dysplasia.

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.

beta6 Integrin subunit deficiency alleviates lung injury in a mouse model of bronchopulmonary dysplasia.

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.

Maternal IL-1beta production prevents lung injury in a mouse model of bronchopulmonary dysplasia.

Little is known about the influence of maternal inflammation on neonatal outcome. Production of IL-1beta in the lungs of newborn infants is associated with bronchopulmonary dysplasia. Using bitransgenic (bi-TG) mice in which human (h) IL-1beta is expressed with a doxycycline-inducible system controlled by the Clara cell secretory protein promoter, we have shown that hIL-1beta expression causes a bronchopulmonary dysplasia-like illness in infant mice. To study the hypothesis that maternal hIL-1beta production modifies the response of the newborn to hIL-1beta, doxycycline was administered to bi-TG and control dams from Embryonic Day 0, inducing production of hIL-1beta by the bi-TG dams before hIL-1beta production started in their bi-TG fetuses, or from Embryonic Day 15, inducing simultaneous production of hIL-1beta by both the bi-TG dams and their bi-TG fetuses. In addition to the lungs, hIL-1beta was expressed at low levels in the uteri of bi-TG dams. Maternal inflammation preceding fetal inflammation increased the survival and growth of hIL-1beta-expressing pups, enhanced alveolarization, and protected the airways against remodeling and goblet cell hyperplasia. Maternal hIL-1beta production preceding fetal hIL-1beta production caused silencing of several inflammatory genes, including CXC and CC chemokines, murine IL-1beta, serum amyloid A3, and Toll-like receptors 2 and 4, and suppressed the expression of chitinase-like lectins Ym1 and Ym2 in the lungs of infant mice. Maternal inflammation protects the newborn against subsequent hIL-1beta-induced lung inflammation and injury. In contrast, induction of hIL-1beta production simultaneously in bi-TG dams and their fetuses offered no protection against inflammatory lung disease in the neonate.

Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia.

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.

IL-1beta disrupts postnatal lung morphogenesis in the mouse.

Pulmonary inflammation and increased production of the inflammatory cytokine IL-1beta are associated with the development of bronchopulmonary dysplasia (BPD) in premature infants. To study the actions of IL-1beta in the fetal and newborn lung in vivo, we developed a bitransgenic mouse in which IL-1beta is expressed under conditional control in airway epithelial cells. Perinatal pulmonary expression of IL-1beta caused respiratory insufficiency that was associated with increased postnatal mortality. While intrauterine growth of IL-1beta-expressing mice was normal, their postnatal growth was impaired. IL-1beta disrupted alveolar septation and caused abnormalities in alpha-smooth muscle actin and elastin deposition in the septa of distal airspaces. IL-1beta disturbed capillary development and inhibited the production of vascular endothelial growth factor in the lungs of infant mice. IL-1beta induced the expression of CXC chemokines KC (CXCL1) and macrophage inflammatory protein-2 (CXCL2) and of CC chemokines monocyte chemotactic protein (MCP)-1 (CCL2) and MCP-3 (CCL7), consistent with neutrophilic and monocytic infiltration of the lungs. IL-1beta caused goblet cell metaplasia and bronchial smooth muscle hyperplasia. Perinatal expression of IL-1beta in epithelial cells of the lung caused a lung disease that was clinically and histologically similar to BPD.