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Papers by Meera Subramaniam

M. Subramaniam and C. Steiner contributed equally to this paper and both should be considered as ... more M. Subramaniam and C. Steiner contributed equally to this paper and both should be considered as equivalent first authors. 11 Author to whom correspondence should be addressed:

The Journal of Allergy and Clinical Immunology: In Practice, 2019

The use of tocilizumab in two children with severe persistent, steroid-resistant asthma resulted ... more The use of tocilizumab in two children with severe persistent, steroid-resistant asthma resulted in immunological improvement and suggestive of clinical improvement.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Blood, 2018

Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of... more Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of the lungs after hematopoietic cell transplantation, is characterized by fixed airway obstruction, bronchiolar inflammation, and scarring and confers a dismal prognosis. While steroids are the backbone therapy for BOS, prolonged use is not recommended. There is no consensus therapy for patients who are steroid dependent or refractory (SR). Ruxolitinib, a JAK1/2 inhibitor, has potent anti-inflammatory effects by modifying T and dendritic cell signaling. It is FDA approved to treat acute GVHD, though there are also reports of its efficacy in cGVHD. We describe the experience of children with SR BOS treated with ruxolitinib. Methods: IRB approval was obtained for retrospective review of all patients treated with ruxolitinib for SR BOS after allogenic HCT. Patients were identified using departmental records. BOS was defined as SR if patients had worsening pulmonary function tests (PFTs) on t...

Blood, 2018

Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of... more Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of the lungs after hematopoietic cell transplantation, is characterized by fixed airway obstruction, bronchiolar inflammation, and scarring and confers a dismal prognosis. While steroids are the backbone therapy for BOS, prolonged use is not recommended. There is no consensus therapy for patients who are steroid dependent or refractory (SR). Ruxolitinib, a JAK1/2 inhibitor, has potent anti-inflammatory effects by modifying T and dendritic cell signaling. It is FDA approved to treat acute GVHD, though there are also reports of its efficacy in cGVHD. We describe the experience of children with SR BOS treated with ruxolitinib. Methods: IRB approval was obtained for retrospective review of all patients treated with ruxolitinib for SR BOS after allogenic HCT. Patients were identified using departmental records. BOS was defined as SR if patients had worsening pulmonary function tests (PFTs) on t...

The American journal of pathology, 2017

Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential ef... more Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8(+) effector T cells. The function of PD-L1 ...

which permits unrestricted use, distribution, and reproduction in any medium, provided the origin... more which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC admi...

neuroendocrine cells The pathogenesis of bronchopulmonary dysplasia (BPD) is thought to be multif... more neuroendocrine cells The pathogenesis of bronchopulmonary dysplasia (BPD) is thought to be multifactorial, with prematurity, barotrauma, inflammation, and pulmonary O2 toxicity playing important roles (1). Evidence suggests that an oxidant/antioxidant im-balance exists in lungs that are at risk for BPD. Higher con-centrations of lipid peroxidation metabolites such as F2-isoprostanes have been found in premature infants (2, 3). Infants who develop BPD have elevated endothelin-1 in tracheal aspirates (4), known to prime both neutrophils and macro-phages to produce more superoxide (5). Preterm babies have lower levels of retinoic acid (6), which has been shown to suppress both superoxide and hydrogen peroxide formation in stimulated neutrophils and macrophages (7). Observations (Received in original form March 20, 2002; accepted in final form September 5, 2002)

a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstr... more a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. Objectives: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to ‘‘modern-day BPD.’’ Methods: The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. Measurements and Main Results: In 125-day PRN animals, urine bombesinlike

Blood Advances

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflamm... more Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was obs...

Bone Marrow Transplantation

Journal of Allergy and Clinical Immunology

RATIONALE: To find useful biomarkers for a differential diagnosis between asthma and COPD, we eva... more RATIONALE: To find useful biomarkers for a differential diagnosis between asthma and COPD, we evaluated NAGL (neutrophil gelatinaseassociated lipocalin), sRAGE (soluble receptor for advanced glycosylation end products), and anti-elastin antibody. METHODS: The subjects were patients with asthma (10 men, 14 women; mean age, 67.4 years) and COPD (16 men, 0 women; 74.8 years). Samples from sputum and serum were collected, and NAGL, sRAGE, and antielastin antibody levels were measured. RESULTS: Sputum levels of NAGL were significantly higher in COPD (5.91 6 5.75 mg/mL) than asthma (2.41 6 2.91 mg/mL, p<0.05), although serum levels did not differ significantly (69.0 6 19.8 ng/mL and 67.3 6 27.0 ng/mL, respectively). Neither sputum nor serum levels of sRAGE were significantly different between COPD (0.45 6 0.89 ng/mL and 0.40 6 0.18 ng/mL, respectively) and asthma (0.19 6 0.21 ng/mL and 0.51 6 0.20 ng/mL, respectively). However, levels of anti-elastin antibody were significantly higher in asthma than COPD in sputum (11.0 6 7.3 mg/mL and 5.8 6 5.2 mg/mL, respectively; p <0.05) and serum (44.2 6 77.4 and 10.3 6 22.3 mg/mL, respectively; p<0.05). CONCLUSIONS: NAGL in sputum may be a useful biomarker for COPD. Elastin is found throughout the airways. The production of antielastin antibody in asthma may contribute to airway remodeling via autoimmune inflammation, but not to emphysema in COPD. We are currently analyzing these relationships against patient backgrounds and other data. We will present our final results at the 2018 AAAAI/WAO.

Increased levels of MMP-8 (neutrophil collagenase) have been reported in OB, but the biological r... more Increased levels of MMP-8 (neutrophil collagenase) have been reported in OB, but the biological role of MMP-8 in OB is not known. MMP-8 is an interstitial col- lagenase highly expressed by polymorphonuclear leu- kocytes, which are prominent in early OB. Here, we show that MMP-8 promotes migration of PMNs through the collagen-rich matrix in a mouse heterotopic airway transplant model

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplas... more Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplasia (BPD). In baboon models, anti-BLP blocking antibodies abrogate BPD. We now demonstrate hyperplasia of both neuroendocrine cells and mast cells in lungs of baboons with BPD, compared with non-BPD controls or BLP antibody-treated BPD baboons. To determine whether BLPs are proinflammatory, bombesin was administered intratracheally to mice. Forty-eight hours later, we observed increased numbers of lung mast cells. We analyzed murine mast cells for BLP receptor gene expression, and identified mRNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor (NMB-R), but not gastrin-releasing peptide receptor. Only NMB-R-null mice accumulated fewer lung mast cells after bombesin treatment. Bombesin, gastrin-releasing peptide, NMB, and a bombesin receptor subtype 3-specific ligand induced mast cell proliferation and chemotaxis in vitro. These observations support a role for multiple BLPs in promoting mast cell responses, suggesting a mechanistic link between BLPs and chronic inflammatory lung diseases.

Stem Cells International, 2014

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Journal of Experimental Medicine

The inflammatory response at sites of contact hypersensitivity induced by oxazolone was examined ... more The inflammatory response at sites of contact hypersensitivity induced by oxazolone was examined in the ears of P-selectin-deficient and wild-type mice. Accumulation of CD4 + T lymphocytes, monocytes, and neutrophils was reduced significantly in the mutant mice, as well as mast cell degranulation. In contrast, there was no significant difference in vascular permeability or edema between the two genotypes. The results demonstrate a role for P-selectin in recruitment of CD4 + T lymphocytes and show that P-selectin plays a role in long-term inflammation as well as in acute responses.

Blood

Information about reproducing this article in parts or in its entirety may be found online at:

M. Subramaniam and C. Steiner contributed equally to this paper and both should be considered as ... more M. Subramaniam and C. Steiner contributed equally to this paper and both should be considered as equivalent first authors. 11 Author to whom correspondence should be addressed:

The Journal of Allergy and Clinical Immunology: In Practice, 2019

The use of tocilizumab in two children with severe persistent, steroid-resistant asthma resulted ... more The use of tocilizumab in two children with severe persistent, steroid-resistant asthma resulted in immunological improvement and suggestive of clinical improvement.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Blood, 2018

Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of... more Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of the lungs after hematopoietic cell transplantation, is characterized by fixed airway obstruction, bronchiolar inflammation, and scarring and confers a dismal prognosis. While steroids are the backbone therapy for BOS, prolonged use is not recommended. There is no consensus therapy for patients who are steroid dependent or refractory (SR). Ruxolitinib, a JAK1/2 inhibitor, has potent anti-inflammatory effects by modifying T and dendritic cell signaling. It is FDA approved to treat acute GVHD, though there are also reports of its efficacy in cGVHD. We describe the experience of children with SR BOS treated with ruxolitinib. Methods: IRB approval was obtained for retrospective review of all patients treated with ruxolitinib for SR BOS after allogenic HCT. Patients were identified using departmental records. BOS was defined as SR if patients had worsening pulmonary function tests (PFTs) on t...

Blood, 2018

Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of... more Background: Bronchiolitis obliterans syndrome (BOS), chronic graft versus host (cGVHD) disease of the lungs after hematopoietic cell transplantation, is characterized by fixed airway obstruction, bronchiolar inflammation, and scarring and confers a dismal prognosis. While steroids are the backbone therapy for BOS, prolonged use is not recommended. There is no consensus therapy for patients who are steroid dependent or refractory (SR). Ruxolitinib, a JAK1/2 inhibitor, has potent anti-inflammatory effects by modifying T and dendritic cell signaling. It is FDA approved to treat acute GVHD, though there are also reports of its efficacy in cGVHD. We describe the experience of children with SR BOS treated with ruxolitinib. Methods: IRB approval was obtained for retrospective review of all patients treated with ruxolitinib for SR BOS after allogenic HCT. Patients were identified using departmental records. BOS was defined as SR if patients had worsening pulmonary function tests (PFTs) on t...

The American journal of pathology, 2017

Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential ef... more Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1-deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8(+) effector T cells. The function of PD-L1 ...

which permits unrestricted use, distribution, and reproduction in any medium, provided the origin... more which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC admi...

neuroendocrine cells The pathogenesis of bronchopulmonary dysplasia (BPD) is thought to be multif... more neuroendocrine cells The pathogenesis of bronchopulmonary dysplasia (BPD) is thought to be multifactorial, with prematurity, barotrauma, inflammation, and pulmonary O2 toxicity playing important roles (1). Evidence suggests that an oxidant/antioxidant im-balance exists in lungs that are at risk for BPD. Higher con-centrations of lipid peroxidation metabolites such as F2-isoprostanes have been found in premature infants (2, 3). Infants who develop BPD have elevated endothelin-1 in tracheal aspirates (4), known to prime both neutrophils and macro-phages to produce more superoxide (5). Preterm babies have lower levels of retinoic acid (6), which has been shown to suppress both superoxide and hydrogen peroxide formation in stimulated neutrophils and macrophages (7). Observations (Received in original form March 20, 2002; accepted in final form September 5, 2002)

a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstr... more a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. Objectives: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to ‘‘modern-day BPD.’’ Methods: The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. Measurements and Main Results: In 125-day PRN animals, urine bombesinlike

Blood Advances

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflamm... more Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was obs...

Bone Marrow Transplantation

Journal of Allergy and Clinical Immunology

RATIONALE: To find useful biomarkers for a differential diagnosis between asthma and COPD, we eva... more RATIONALE: To find useful biomarkers for a differential diagnosis between asthma and COPD, we evaluated NAGL (neutrophil gelatinaseassociated lipocalin), sRAGE (soluble receptor for advanced glycosylation end products), and anti-elastin antibody. METHODS: The subjects were patients with asthma (10 men, 14 women; mean age, 67.4 years) and COPD (16 men, 0 women; 74.8 years). Samples from sputum and serum were collected, and NAGL, sRAGE, and antielastin antibody levels were measured. RESULTS: Sputum levels of NAGL were significantly higher in COPD (5.91 6 5.75 mg/mL) than asthma (2.41 6 2.91 mg/mL, p<0.05), although serum levels did not differ significantly (69.0 6 19.8 ng/mL and 67.3 6 27.0 ng/mL, respectively). Neither sputum nor serum levels of sRAGE were significantly different between COPD (0.45 6 0.89 ng/mL and 0.40 6 0.18 ng/mL, respectively) and asthma (0.19 6 0.21 ng/mL and 0.51 6 0.20 ng/mL, respectively). However, levels of anti-elastin antibody were significantly higher in asthma than COPD in sputum (11.0 6 7.3 mg/mL and 5.8 6 5.2 mg/mL, respectively; p <0.05) and serum (44.2 6 77.4 and 10.3 6 22.3 mg/mL, respectively; p<0.05). CONCLUSIONS: NAGL in sputum may be a useful biomarker for COPD. Elastin is found throughout the airways. The production of antielastin antibody in asthma may contribute to airway remodeling via autoimmune inflammation, but not to emphysema in COPD. We are currently analyzing these relationships against patient backgrounds and other data. We will present our final results at the 2018 AAAAI/WAO.

Increased levels of MMP-8 (neutrophil collagenase) have been reported in OB, but the biological r... more Increased levels of MMP-8 (neutrophil collagenase) have been reported in OB, but the biological role of MMP-8 in OB is not known. MMP-8 is an interstitial col- lagenase highly expressed by polymorphonuclear leu- kocytes, which are prominent in early OB. Here, we show that MMP-8 promotes migration of PMNs through the collagen-rich matrix in a mouse heterotopic airway transplant model

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplas... more Bombesin-like peptides (BLPs) are elevated in newborns who later develop bronchopulmonary dysplasia (BPD). In baboon models, anti-BLP blocking antibodies abrogate BPD. We now demonstrate hyperplasia of both neuroendocrine cells and mast cells in lungs of baboons with BPD, compared with non-BPD controls or BLP antibody-treated BPD baboons. To determine whether BLPs are proinflammatory, bombesin was administered intratracheally to mice. Forty-eight hours later, we observed increased numbers of lung mast cells. We analyzed murine mast cells for BLP receptor gene expression, and identified mRNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor (NMB-R), but not gastrin-releasing peptide receptor. Only NMB-R-null mice accumulated fewer lung mast cells after bombesin treatment. Bombesin, gastrin-releasing peptide, NMB, and a bombesin receptor subtype 3-specific ligand induced mast cell proliferation and chemotaxis in vitro. These observations support a role for multiple BLPs in promoting mast cell responses, suggesting a mechanistic link between BLPs and chronic inflammatory lung diseases.

Stem Cells International, 2014

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival... more Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex-(MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Journal of Experimental Medicine

The inflammatory response at sites of contact hypersensitivity induced by oxazolone was examined ... more The inflammatory response at sites of contact hypersensitivity induced by oxazolone was examined in the ears of P-selectin-deficient and wild-type mice. Accumulation of CD4 + T lymphocytes, monocytes, and neutrophils was reduced significantly in the mutant mice, as well as mast cell degranulation. In contrast, there was no significant difference in vascular permeability or edema between the two genotypes. The results demonstrate a role for P-selectin in recruitment of CD4 + T lymphocytes and show that P-selectin plays a role in long-term inflammation as well as in acute responses.

Blood

Information about reproducing this article in parts or in its entirety may be found online at: