Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

The Influence of the Superficial Venous System on DIEP Flap Drainage in Breast Reconstruction.

BACKGROUND: Autologous tissue has become the gold standard in breast reconstruction. The use of a deep inferior epigastric perforator (DIEP) flap has the advantages of giving a natural appearance to the reconstructed breast and being associated with lower morbidity at the donor site when compared with the transverse rectus abdominis myocutaneous flap. Venous complications such as venous thrombosis and insufficiency remain the main causes of flap loss and surgical revisions. The aim of this study was to evaluate the influence of superficial venous drainage of the DIEP flap and the addition of a second venous anastomosis have on flap survival. METHODS: This was a retrospective cohort study collected from a prospective database maintained by our institution. Data was obtained from the medical records of female patients who underwent mastectomy and breast reconstruction with a DIEP flap between March 2010 and March 2017. We evaluated 137 DIEP patients with unilateral breast reconstructions. In 64 (46.7%) the deep venous system was chosen and 73 (53.3%) had an additional superficial vein anastomosed. RESULTS: Out of the 137 patients evaluated, there were 16 (11.67%) cases of revision, 14 (10.21%) were due to venous thrombosis. Twelve cases (8.75%) of flap loss were reported. Reoperation rate was lower in the dual venous drainage group when compared with the single venous drainage group (p = 0.005), as was the rate of flap loss (p = 0.006) and reoperation due to venous thrombosis (p = 0.002). Out of the 125 DIEP flaps, fat necrosis was clinically identified in 7 (5.1%) cases, and the rate was lower in the dual venous drainage system group (p = 0.01). CONCLUSION: Dual venous drainage of a DIEP flap appears to reduce the rates of venous thrombosis, reoperation, total flap loss, and fat necrosis.

Evaluation of Factors Associated with, and Outcomes for Patients with Nonhome Discharge Destinations Following Carotid Endarterectomy.

INTRODUCTION: Following a carotid endarterectomy (CEA) procedure, patients are discharged to their homes or other locations than home such as an acute care facility or skilled nursing facility based on their functional status and level of medical attention needed. Decision-making for discharge destination following a CEA to home or nonhome locations is important due to the differences in survival and postoperative complications. While primary outcomes such as mortality and occurrence of stroke following CEA have been extensively studied, there is a paucity of information characterizing outcomes of discharge destination and the factors associated. The purpose of this study was to explore the factors associated with discharge to nonhome destinations after CEA, and outcomes after discharge. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, we identified patients who underwent CEA from 2011 to 2018. Patients were divided into two groups based on their discharge destination (home versus nonhome). Univariate and multivariate analysis were performed for preoperative and intraoperative factors associated with different discharge destinations. Postoperative complications associated with discharge to nonhome destinations were analyzed and mortality after discharge from hospital was compared between the 2 groups. RESULTS: A total of 25,094 patients met the criteria for inclusion in the study, of which 39% were females and 61% were males; median age was 71 years. Twenty four thousand one hundred twenty-five patients (93.13%) were discharged to home (Group I) and 1,779 (6.87%) were discharged to nonhome destinations (Group II). Following preoperative and intraoperative factors were associated with discharge to nonhome locations: older age, diabetes mellitus, functional independent status, transfer from other hospitals, symptomatic status, need for preoperative blood transfusions, severe ipsilateral carotid stenosis, elective CEA, need for intraoperative shunt and general anesthesia (all P< 0.05). Following postoperative complications had statistically significant association with discharge to nonhome destinations: postoperative blood transfusion, pneumonia, unplanned intubation, longer than 48 hours on ventilator, development of stroke, myocardial infarction, deep vein thrombosis, and sepsis (all P< 0.05). Mortality after discharge from hospital was 0.39% (n = 100). Mortality among those who were discharged to home was 0.29% vs. 1.63% for those who were discharged to nonhome locations (P< 0.05). CONCLUSIONS: Majority of the patients after CEA are discharged back to their homes. This study identifies the factors which predispose patients discharged to locations, other than home. Patients who are not discharged home have higher mortality as compared to those who are discharged to their homes.

Mapeamento anatômico das anomalias vasculares dos lábios / Anatomical mapping of vascular anomalies of the lips

Introdução: O lábio é a região do corpo mais frequentemente acometida por anomalias vasculares (AV). A correta determinação da etiologia da lesão é determinante à escolha do tratamento do paciente e à correta condução do caso. O objetivo deste estudo é correlacionar o posicionamento anatômico e as características das lesões com o diagnóstico etiológico das AVs dos lábios, a fim de promover uma ferramenta que auxilie na prática clínica. Métodos: Análise retrospectiva de 150 pacientes com AV dos lábios, avaliados entre 1999 e 2017. O diagnóstico etiológico foi baseado na classificação de ISSVA 2014. Análise clínica e fotográfica foi realizada para avaliar o padrão anatômico de envolvimento e mapear as lesões. Resultados: Hemangioma infantil apresentou acometimento de apenas um lábio, em menor extensão e situado mais centralmente, com raro envolvimento de comissura oral. Malformações venosas e venolinfáticas (MVs) e malformações arteriovenosas (MAVs) envolveram o lábio superior predominantemente, situadas mais lateralmente e acarretando significativa deformidade. Contudo, MAVs apresentaram mais frequente extensão além dos limites do vermelhão. Os pacientes com malformações capilares (MCs) sofriam de acometimento integral do lábio inferior. Todos os casos de malformações linfáticas exclusivas (MLs) envolveram o lábio superior inteiro, com grande distorção. Conclusão: A apresentação inicial das AVs muitas vezes consiste em pequenas alterações, desafiadoras ao diagnóstico assertivo. Padrões específicos de acometimentos foram observados para cada diagnóstico etiológico estudado. O mapeamento pode ser utilizado como ferramenta auxiliar diagnóstica e contribuir para melhor intervenção nos pacientes com anomalias vasculares labiais.

Introduction: The lip is the body region more often affected by vascular anomalies (VAs). Identifying the appropriate etiology of the lesion is significantly important when determining the treatment of choice for the patient. This study aimed to determine the association between the anatomical positioning and the characteristics of the lesions and the etiological diagnosis of VAs of the lips to identify the appropriate tool to be used in clinical practice. Methods: A retrospective analysis was performed in 150 patients with VA of the lips evaluated between 1999 and 2017. The etiological diagnosis was based on the International Society for the Study of Vascular Anomalies 2014 classification. Clinical and photographic analysis was performed to assess the anatomical pattern of involvement and map the lesions. Results: An infantile hemangioma was observed to a lesser extent in only one lip and was situated more centrally, with rare involvement of the labial commissure. Venous and venous-lymphatic malformations and arteriovenous malformations (AVMs) involving the upper lip were predominantly located more laterally and caused significant deformity. However, AVMs more often extended beyond the limits of the vermilion. Capillary malformations were observed in the entire lower lip in some patients. Simple lymphatic malformations were observed in the entire upper lip with significant distortion in some patients. Conclusion: The initial presentation of VAs often comprises minimal changes; hence, establishing an assertive diagnosis is considered difficult. Specific patterns of involvement were observed for each etiological diagnosis studied. Anatomical mapping can be used as an auxiliary diagnostic tool and can possibly identify an appropriate clinical intervention in patients with VAs of the lip.

Retalho romboide triplo para fechamento de defeitos em couro cabeludo / Use of three rhomboid flaps for scalp defect coverage

Full-thickness scalp defects exposing the skull can be challenging for plastic surgeons. Scalp skin has low elasticity, so a large flap is necessary to cover even a small defect. This article presents 9 cases in which 3 rhomboid flaps were used for the c1osure of scalp defects. One patient experienced flap necrosis and required reoperation. Two other patients had minor complications treated with dressing. The method presented here in allows the harvest of 3 small flaps that collectively cover the defect as well as the primary closure of the donor area. This technique does not require the creation of a large fiap or skin graft from the donor. Thus, the technique described here in is suitable for medium-thickness scalp defects and is a good alternative to large rotation fiaps and skin grafts.

Defeitos no couro cabeludo podem ser um desafio para os cirurgiões plásticos quando afetam sua espessura total e deixam o crânio exposto. O couro cabeludo tem pouca elasticidade,assim um grande retalho é necessário para cobrir um defeito pequeno. O objetivo deste artigo é apresentar 9 casos em que 3 retalhos romboides foram utilizados para o fechamento de defeitos no couro cabeludo. Um paciente apresentou necrose do retalho e foi necessária reoperação. Dois outros pacientes tiveram complicações menores, que foram tratadas com curativos. O método apresentado permite a confecção de 3 pequenos retalhos que em conjunto cobrem o defeito, e as áreas doadoras são fechadas primariamente. Com a utilização da técnica descrita, a confecção de um retalho grande e a enxertia de pele da área doadora não são necessárias. Neste artigo é descrita uma técnica para fechamento de defeitos de tamanho moderado no couro cabeludo, que é uma boa alternativa a grandes retalhos de rotação ou enxerto de pele.

A transgenic TCR directs the development of IL-4+ and PLZF+ innate CD4 T cells.

MHC class II-expressing thymocytes can efficiently mediate positive selection of CD4 T cells in mice. Thymocyte-selected CD4 (T-CD4) T cells have an innate-like phenotype similar to invariant NKT cells. To investigate the development and function of T-CD4 T cells in-depth, we cloned TCR genes from T-CD4 T cells and generated transgenic mice. Remarkably, positive selection of T-CD4 TCR transgenic (T3) thymocytes occurred more efficiently when MHC class II was expressed by thymocytes than by thymic epithelial cells. Similar to polyclonal T-CD4 T cells and also invariant NKT cells, T3 CD4 T cell development is controlled by signaling lymphocyte activation molecule/signaling lymphocyte activation molecule-associated protein signaling, and the cells expressed both IL-4 and promyelocytic leukemia zinc finger (PLZF). Surprisingly, the selected T3 CD4 T cells were heterogeneous in that only half expressed IL-4 and only half expressed PLZF. IL-4- and PLZF-expressing cells were first found at the double-positive cell stage. Thus, the expression of IL-4 and PLZF seems to be determined by an unidentified event that occurs postselection and is not solely dependent on TCR specificity or the selection process, per se. Taken together, our data show for the first time, to our knowledge, that the TCR specificity regulates but does not determine the development of innate CD4 T cells by thymocytes.

Detecção de trombose venosa em retalhos livres por medidas de glicemia capilar / Detection of venous thrombosis in free flaps by measurement of capillary blood glucose", "_e": "n

INTRODUÇÃO: A monitorização do retalho livre após a cirurgia é de vital importância, especialmente nas primeiras horas de pós-operatório, pois o momento de reabordagem pode ser o definidor entre o salvamento ou a perda do retalho. Até o momento, não existe trabalho na literatura estudando a decisão de abordagem do retalho baseada em medidas objetivas ou a comparação da glicemia entre retalhos que evoluíram bem com os que sofreram sofrimento vascular. O objetivo deste estudo é avaliar a validade da medida da glicemia capilar do retalho como método de monitorização de retalhos microcirúrgicos comparando com a avaliação clínica. MÉTODO: Foram estudados prospectivamente 16 pacientes portadores de retalhos livres, realizados de maio de 2012 a julho de 2012. A glicemia capilar foi avaliada por equipe formada por profissionais não envolvidos com a cirurgia realizada. A avaliação clínica do retalho foi realizada no pós-operatório imediato, na chegada à UTI, a cada 3 horas e sempre que necessário. RESULTADOS: Dos 16 pacientes, 5 (31,3%) apresentaram complicações nas primeiras 24 horas. Todas as complicações observadas foram trombose venosa. Foi observada diferença estatisticamente significante na glicemia capilar de portadores de retalhos que apresentaram trombose venosa em comparação àqueles que não tiveram a complicação, nas medidas realizadas 6 horas, 9 horas e 12 horas após a operação (P < 0,05). CONCLUSÕES: A medida da glicemia capilar não foi superior à avaliação clínica por profissional experiente na detecção de trombose venosa de retalhos livres.

BACKGROUND: Monitoring of free flaps after surgery is vitally important, especially in the first few hours because the timing of reoperation can determine flap salvage or loss. To date, no study has examined the decision to reoperate on a flap based on the objective measure of glycemia or a comparison between flaps that showed good outcomes and those that showed vascular damage. The objective of this study was to evaluate the validity of blood glucose measurements within the flap as a method for monitoring free flaps and to compare the efficacy of this method with that of clinical assessments. METHODS: The study was prospective, included 16 patients with free flaps, and was conducted from May 2012 to July 2012. A team of professionals not involved in the surgery evaluated capillary glycemia. Flaps were clinically evaluated during the immediate postoperative period, on ICU admission, at every 3 hours, and as needed. RESULTS: Of the 16 patients, 5 (31.3%) had venous thrombosis in the first 24 hours. Statistically significant differences were noted in capillary glycemia in patients with or without venous thrombosis in measurements obtained 6, 9, and 12 hours after surgery (P < 0.05). CONCLUSIONS: The measurement of capillary glycemia was not superior to clinical evaluation by an experienced professional for the detection of venous thrombosis within free flaps.

Evaluation of serial C-reactive protein measurements after surgical treatment of pleural empyema.

OBJECTIVE: Serial C-reactive protein measurements have been used to diagnose and monitor the response to therapy in patients with pneumonia and other infectious diseases. Nonetheless, the role of C-reactive protein measurement after surgical treatment for pleural empyema is not well defined. The aim of this study is to describe the behavior of C-reactive protein levels after the surgical treatment of pleural empyema and to correlate this parameter with the patient's prognosis. METHODS: We retrospectively analyzed the records of patients with pleural empyema treated by either chest-tube drainage or surgery from January 2006 to December 2008. C-reactive protein levels were recorded preoperatively and 2 and 7 days postoperatively. The clinical outcome was binary: success or failure (mortality or the need for repeated pleural intervention). RESULTS: The study group comprised fifty-two patients. The median C-reactive protein values were as follows: 146 mg/L (pre-operative), 134 mg/L (post-operative day 2), and 116 mg/L (post-operative day 7). There was a trend toward a decrease in these values during the first week after surgery, but this difference was only statistically significant on day 7 after surgery. Over the first week after surgery, the C-reactive protein values decreased similarly in both groups (successful and failed treatment). No correlation between the preoperative C-reactive protein level and the clinical outcome was found. CONCLUSIONS: We observed that, in contrast to other medical conditions, C-reactive protein levels fall slowly during the first postoperative week in patients who have undergone surgical treatment for pleural empyema. No correlation between the perioperative C-reactive protein level and the clinical outcome was observed.

Evaluation of serial C-reactive protein measurements after surgical treatment of pleural empyema

OBJECTIVE: Serial C-reactive protein measurements have been used to diagnose and monitor the response to therapy in patients with pneumonia and other infectious diseases. Nonetheless, the role of C-reactive protein measurement after surgical treatment for pleural empyema is not well defined. The aim of this study is to describe the behavior of C-reactive protein levels after the surgical treatment of pleural empyema and to correlate this parameter with the patient's prognosis. METHODS: We retrospectively analyzed the records of patients with pleural empyema treated by either chest-tube drainage or surgery from January 2006 to December 2008. C-reactive protein levels were recorded preoperatively and 2 and 7 days postoperatively. The clinical outcome was binary: success or failure (mortality or the need for repeated pleural intervention). RESULTS: The study group comprised fifty-two patients. The median C-reactive protein values were as follows: 146 mg/L (pre-operative), 134 mg/L (post-operative day 2), and 116 mg/L (post-operative day 7). There was a trend toward a decrease in these values during the first week after surgery, but this difference was only statistically significant on day 7 after surgery. Over the first week after surgery, the C-reactive protein values decreased similarly in both groups (successful and failed treatment). No correlation between the preoperative C-reactive protein level and the clinical outcome was found. CONCLUSIONS: We observed that, in contrast to other medical conditions, C-reactive protein levels fall slowly during the first postoperative week in patients who have undergone surgical treatment for pleural empyema. No correlation between the perioperative C-reactive protein level and the clinical outcome was observed.

Triggering receptor expressed on myeloid cells-1 (TREM-1) modulates immune responses to Aspergillus fumigatus during fungal asthma in mice.

Triggering receptor expressed on myeloid cells-1 (TREM-1) expression is increased during pulmonary fungal infection suggesting that this receptor might be involved in anti-fungal immune responses. To address the role of TREM-1 in a murine model of fungal allergic airway disease, A. fumigatus-sensitized CBA/J mice received by intratracheal injection a mixture of live A. fumigatus conidia and one of a control adenovirus vector (Ad70), an adenovirus containing a gene encoding for the extracellular domain of mouse TREM-1 and the F(c) portion of human IgG (AdTREM-1Ig; a soluble inhibitor of TREM-1 function), or an adenovirus containing mouse DAP12 (AdDAP12; DAP12 is an intracellular adaptor protein required for TREM-1 signaling), and examined at various days after challenge. Whole lung TREM-1 levels peaked at day 3 whereas circulating TREM-1 levels peaked at day 30 in this fungal asthma model. AdTREM-1Ig-treated mice exhibited significantly higher airway hyperresponsiveness following methacholine challenge compared with Ad70- and AdDAP12-treated mice. Whole lung analysis of AdTREM-1Ig treated mice revealed markedly higher amounts of fungal material compared with the other groups. ELISA analysis of whole lung and bronchoalveolar lavage samples indicated that several pro-allergic cytokine and chemokines including CCL17 and CCL22 were significantly increased in the AdTREM-1Ig group compared with the other groups. Finally, Pam3Cys and soluble Aspergillus antigens induced TREM-1 transcript expression in macrophages in a TLR2 dependent manner. In conclusion, TREM-1 modulates the immune response directed against A. fumigatus during experimental fungal asthma.

Unique methylation pattern of oncostatin m receptor gene in cancers of colorectum and other digestive organs.

PURPOSE: Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined. EXPERIMENTAL DESIGN: Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza-2-deoxycytidine or DNA methyltransferase 1 small interfering RNA or a histone deacetylase inhibitor trichostatin A. OSMR mRNA level was determined by reverse transcription-PCR. The acetylation of histone H3 was analyzed by chromatin immunoprecipitation assay. RESULTS: We observed methylation of OSMR in 88 of 98 (90%) colorectal cancers, 34 of 38 (89%) colorectal polyps, 17 of 31 (55%) normal-appearing mucosa adjacent to colorectal cancers, 13 of 40 (33%) gastric cancers, and 2 of 10 (20%) pancreatic cancers. OSMR methylation was absent or rarely detected in normal colonic mucosa from noncancer patients or in cancers of nondigestive organs, including breast, lung, liver, prostate, kidney, and melanoma. We observed a significant correlation between OSMR methylation and loss of mRNA expression in 39 cancer cell lines. Following the treatment of colorectal cancer cell lines with 5-aza-2-deoxycytidine, DNA methyltransferase 1 small interfering RNA, or trichostatin A, the induction of OSMR mRNA and the enrichment in the level of histone acetylation were observed. CONCLUSIONS: The epigenetic silencing and DNA methylation of OSMR occur frequently in colorectal cancers and rarely in cancers of nondigestive organs. OSMR methylation is an early event in the colorectal carcinogenesis.

Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa.

Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates survival, proliferation, differentiation, and function of myeloid cells. Recently, GM-CSF has been shown to be important for normal pulmonary homeostasis. We report that GM-CSF is induced in lung leukocytes during infection with Gram-negative bacteria. Therefore, we postulated that deficiencies in GM-CSF would increase susceptibility to Gram-negative infection in vivo. After an intratracheal inoculum with Pseudomonas aeruginosa, GM-CSF-/- mice show decreased survival compared with wild-type mice. GM-CSF-/- mice show increased lung, spleen, and blood bacterial CFU. GM-CSF-/- mice are defective in the production of cysteinyl leukotrienes, prostaglandin E2, macrophage inflammatory protein, and keratinocyte-derived chemokine in lung leukocytes postinfection. Despite these defects, inflammatory cell recruitment is not diminished at 6 or 24 h postinfection, and the functional activity of polymorphonuclear leukocytes from the lung and peritoneum against P. aeruginosa is enhanced in GM-CSF-/- mice. In contrast, alveolar macrophage (AM) phagocytosis, killing, and H2O2 production are defective in GM-CSF-/- mice. Although the absence of GM-CSF has profound effects on AMs, peritoneal macrophages seem to have normal bactericidal activities in GM-CSF-/- mice. Defects in AM function may be related to diminished levels of IFN-gamma and TNF-alpha postinfection. Thus, GM-CSF-/- mice are more susceptible to lung infection with P. aeruginosa as a result of impaired AM function.

Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway.

Molecular and cellular studies of the mechanisms underlying mammalian learning and memory have focused almost exclusively on postsynaptic function. We now reveal an experience-dependent presynaptic mechanism that modulates learning and synaptic plasticity in mice. Consistent with a presynaptic function for endogenous H-ras/extracellular signal-regulated kinase (ERK) signaling, we observed that, under normal physiologic conditions in wild-type mice, hippocampus-dependent learning stimulated the ERK-dependent phosphorylation of synapsin I, and MEK (MAP kinase kinase)/ERK inhibition selectively decreased the frequency of miniature EPSCs. By generating transgenic mice expressing a constitutively active form of H-ras (H-rasG12V), which is abundantly localized in axon terminals, we were able to increase the ERK-dependent phosphorylation of synapsin I. This resulted in several presynaptic changes, including a higher density of docked neurotransmitter vesicles in glutamatergic terminals, an increased frequency of miniature EPSCs, and increased paired-pulse facilitation. In addition, we observed facilitated neurotransmitter release selectively during high-frequency activity with consequent increases in long-term potentiation. Moreover, these mice showed dramatic enhancements in hippocampus-dependent learning. Importantly, deletion of synapsin I, an exclusively presynaptic protein, blocked the enhancements of learning, presynaptic plasticity, and long-term potentiation. Together with previous invertebrate studies, these results demonstrate that presynaptic plasticity represents an important evolutionarily conserved mechanism for modulating learning and memory.

Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia.

Abnormal proliferation of pulmonary fibroblasts is a prominent feature of chronic pulmonary fibrotic diseases such as idiopathic interstitial pneumonia (IIP), but it is not presently clear how this proliferative response by lung fibroblasts can be therapeutically modulated. In the present study, we examined whether it was possible to selectively target primary human pulmonary fibroblasts grown out of surgical lung biopsies (SLBs) from IIP patients based on their expression of interleukin-4 receptor (IL-4R) and IL-13R subunits. Pulmonary fibroblast lines cultured from patients with the severest form of IIP, namely usual interstitial pneumonia, exhibited the greatest gene and protein expression of IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2 compared with primary pulmonary fibroblast lines grown from other IIP SLBs and normal SLBs. When exposed to increasing concentrations of a chimeric protein comprised of human IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), the proliferation of primary usual interstitial pneumonia fibroblasts was inhibited to a much greater extent compared with fibroblast lines from nonspecific interstitial pneumonia and respiratory bronchiolitis/interstitial lung disease patient groups. Fibroblasts from normal patients exhibited minimal susceptibility to the cytotoxic effect of IL13-PE. IL13-PE-mediated targeting of IIP fibroblasts was dependent on their expression of IL-4Ralpha and IL-13Ralpha2. Thus, these data suggest that the abnormal proliferative properties of human lung fibroblasts from certain IIP patient groups can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells.

Impact of interleukin-13 responsiveness on the synthetic and proliferative properties of Th1- and Th2-type pulmonary granuloma fibroblasts.

Interleukin-13 (IL-13) has emerged as a major cytokine mediator of fibroblast activation and pulmonary fibrosis. Normal (from noninflamed lung), Th1-type (induced by the pulmonary embolization of purified peptide derivative-coated beads in mice sensitized to purified peptide derivative), and Th2-type (induced by the pulmonary embolization of Schistosoma mansoni egg antigen-coated beads in mice sensitized with S. mansoni eggs) primary fibroblast cell lines all exhibited constitutive gene expression of two receptor chains that bind and signal IL-13-mediated cellular events: IL-4Ralpha and IL-13Ralpha1. However, all three fibroblast cell lines exhibited divergent synthetic and proliferative responses to the exogenous addition of either recombinant IL-13 or a chimeric protein comprised of IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), which targets and kills IL-13 receptor overexpressing cells. The exogenous addition of IL-13 to Th1-type and Th2-type fibroblast cultures significantly increased the cellular expression of IL-13Ralpha2, which may function as an IL-13 decoy receptor. After a 24-hour exposure to IL-13, the total collagen generation and cellular proliferation by Th2-type fibroblasts were significantly higher than that observed in similar numbers of normal and Th1-type fibroblasts. In addition IL13-PE, which binds with highest affinity to IL-13Ralpha2, exhibited down-regulatory effects on proliferation and matrix generation expression by Th1- and Th2-type, but not normal, fibroblasts. Thus, these data demonstrate that fibroblasts derived from murine pulmonary granulomas exhibit divergent expression of functional IL-13 receptor and this expression dictates the responsiveness and susceptibility to recombinant IL-13 and IL-13 immunotoxin, respectively.