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Papers by Martin Zamora

Annals of the American Thoracic Society, 2014

Journal of Surgical Research, 2006

RT 1A 1) recipients. Some recipients (n Ն5 per time point) were given cyclosporine A(CsA, 10 mg/k... more RT 1A 1) recipients. Some recipients (n Ն5 per time point) were given cyclosporine A(CsA, 10 mg/kg/day x 5 days, then 5 mg/kg/ every other day until sacrifice), while others (n Ն5) received both CsA and 1.0 ϫ 10 8 unmodified donor BM cells per rat on the day of transplant (CsA ϩ BM). Animals were sacrificed at two weeks and 6 months posttransplant. Leukocytes from the bronchoalveolar lavage (BAL) fluid of the lung graft, native lung, peripheral blood, BM and thymus were collected. Four-color flow cytometry was used to analyse cell phenotypes. Results: At 6 months after transplant, only 4 of 11 lung grafts (36%) in the control versus 8 of 10 grafts (80%) in the BM-treated animals were accepted (pϽ0.05). At two weeks, BM infusion increased total donorderived leukocytes (10.3% vs. 6.6%) and donor-derived dendritic cells (DC, 3.7% vs. 1.0%) in the graft. At 6 months, there was no difference in donor-derived cell numbers or lineages. However, host derived CD4 (15.6% vs. 27.6%; pϭ0.08) and DC (4.5% vs. 9.1%; pϭ0.03) were reduced in lung grafts of BM-treated animals. Conclusion: Donor BM infusion increases the trafficking of donor cells to lung grafts in early stage, and decreases the infiltration of host CD4 and DCs in long-surviving grafts. These findings suggest that donor BM infusion has a long-lasting modulatory effect on host alloreactivity, resulting in improved graft survival.

Chest, 1994

Ft;utsE 2. Tile cysts are composed ofa single layer ofcuboidal cells and a tilin fibrovascular st... more Ft;utsE 2. Tile cysts are composed ofa single layer ofcuboidal cells and a tilin fibrovascular stronla (henlatoxvhin-eosin, original nlagni-fIcation x 47).

European Respiratory Journal, 2004

Surgical advances, in conjunction with more effective immunosuppressive strategies, have propelle... more Surgical advances, in conjunction with more effective immunosuppressive strategies, have propelled the field of lung transplantation forward and have made intermediate-term survival an achievable goal. Nonetheless, the post-transplant course is often marked by complications that threaten both the quality and duration of the recipient9s life. Many of the medical complications that arise are the direct consequence of the need to administer potent immunosuppressive agents, with their attendant risks of infection, malignancy and drug toxicity. This article will review the major medical complications, excluding allograft rejection, which may be encountered in the lung transplant recipient. Familiarity with, and vigilance for, these problems should facilitate earlier recognition, more expeditious intervention and more favourable outcomes.

Therapeutic Advances in Chronic Disease, 2021

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due t... more Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, ...

Cellular immunology, Jan 7, 2018

The induction of tolerance to transplanted organs is a major objective in transplantation immunol... more The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance. By interrogating important adaptive and innate immunity pathways, we demonstrate that the induction of tolerance relies on CD8T-cells. We further demonstrate that αLFA-1 induced tolerance is associated with CD8CD28T-cells with a suppressor phenotype, and that while CD8 cells are present, the effector T-cell response is abrogated. A recent publication has shown that CD8CD28 cells are not diminished by cyclosporine or rapamycin, therefore CD8CD28 cells represent a clinically relevant population. To our knowledge, this is the first time that a mechanism for αLFA-1 induced toler...

Annals of the American Thoracic Society, 2017

Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including pri... more Lung ischemia-reperfusion (IR) injury contributes to post-transplant complications, including primary graft dysfunction. Decades of reports show that reactive oxygen species generated during lung IR contribute to pulmonary vascular endothelial barrier disruption and edema formation, but the specific target molecule(s) that "sense" injury-inducing oxidant stress to activate signaling pathways culminating in pathophysiologic changes have not been established. This review discusses evidence that mitochondrial DNA (mtDNA) may serve as a molecular sentinel wherein oxidative mtDNA damage functions as an upstream trigger for lung IR injury. First, the mitochondrial genome is considerably more sensitive than nuclear DNA to oxidant stress. Multiple studies suggest that oxidative mtDNA damage could be transduced to physiologic dysfunction by pathways that are either a direct consequence of mtDNA damage per se or involve formation of proinflammatory mtDNA damage-associated molecular patterns. Second, transgenic animals or cells overexpressing components of the base excision DNA repair pathway in mitochondria are resistant to oxidant stress-mediated pathophysiologic effects. Finally, published and preliminary studies show that pharmacologic enhancement of mtDNA repair or mtDNA damage-associated molecular pattern degradation suppresses reactive oxygen species-induced or IR injury in multiple organs, including preclinical models of lung procurement for transplant. Collectively, these findings point to the interesting prospect that pharmacologic enhancement of DNA repair during procurement or ex vivo lung perfusion may increase the availability of lungs for transplant and reduce the IR injury contributing to primary graft dysfunction.

European Respiratory Journal, Sep 1, 2012

Case Reports in Transplantation, 2015

Because of the high incidence of morbidity and mortality associated with invasive fungal infectio... more Because of the high incidence of morbidity and mortality associated with invasive fungal infections, antifungal prophylaxis is often used in solid organ transplant recipients. However, this prophylaxis is not universally effective and may contribute to the selection of emerging, resistant pathogens. Here we present a rare case of invasive infection caused byMicroascus trigonosporusspecies complex in a human, which developed during voriconazole prophylaxis in a lung transplant recipient. Nebulized liposomal amphotericin B was used in addition to systemic therapy in order to optimize antifungal drug exposure; this regimen appeared to reduce the patient’s fungal burden. Despite this apparent improvement, the patient’s pulmonary status progressively declined in the setting of multiple comorbidities, ultimately leading to respiratory failure and death.

Cellular Immunology, 2015

Fas Ligand limits inflammatory injury and permits allograft survival by inducing apoptosis of Fas... more Fas Ligand limits inflammatory injury and permits allograft survival by inducing apoptosis of Fasbearing lymphocytes. Previous studies have shown that the CD4 + T-cell is both sufficient and required for murine cardiac allograft rejection. Here, utilizing a transgenic mouse that overexpresses Fas Ligand specifically on cardiomyocytes as heart donors, we sought to determine if Fas Ligand on graft parenchymal cells could resist CD4 + T-cell mediated rejection. When transplanted into fully immunocompetent BALB/c recipients Fas Ligand transgenic hearts were acutely rejected. However, when transplanted into CD4 + T-cell reconstituted BALB/c-rag-/recipients, Fas Ligand hearts demonstrated long-term survival. These results indicate that Fas Ligand over-expression on cardiomyocytes can indeed resist CD4 + T-cell mediated cardiac rejection and suggests contact dependence between Fas Ligand expressing graft parenchymal cells and the effector CD4 + T-cells.

The Journal of Heart and Lung Transplantation, 2015

The Annals of Thoracic Surgery, 2014

Current Transplantation Reports, 2014

Lung transplantation has become an important therapeutic option for patients with end-stage organ... more Lung transplantation has become an important therapeutic option for patients with end-stage organ dysfunction; however, its clinical usefulness has been limited by the relatively early onset of chronic allograft dysfunction and progressive clinical decline. Obliterative bronchiolitis is characterized histologically by luminal fibrosis of the respiratory bronchioles and clinically by bronchiolitis obliterans syndrome (BOS) which is defined by a measured decline in lung function based on forced expiratory volume (FEV 1). Since its earliest description, a number of risk factors have been associated with the development of BOS, including acute rejection, lymphocytic bronchiolitis, primary graft dysfunction, infection, donor specific antibodies, and gastroesophageal reflux disease. However, despite this broadened understanding, the pathogenesis underlying BOS remains poorly understood and once begun, there are relatively few treatment options to battle the progressive deterioration in lung function.

Transplantation, 2010

Background-CD4 T cells can suffice as effector cells to mediate primary acute cardiac allograft r... more Background-CD4 T cells can suffice as effector cells to mediate primary acute cardiac allograft rejection. While CD4 T cells can readily kill appropriate target cells in vitro, the corresponding role of such cytolytic activity for mediating allograft rejection in vivo is unknown. Therefore, we determined whether the cytolytic effector molecules perforin and/or FasL (CD95L) were necessary for CD4 T cell-mediated rejection in vivo. Methods-Wild type C3H(H-2 k) or Fas (CD95)-deficient C3Hlpr (H-2 k) hearts were transplanted into immune-deficient C57B6rag −/− (H-2 b) mice. Recipients then were reconstituted with naïve purified CD4 T cells from either wild-type, perforin (pfp)-deficient, or FasL (gld)-deficient T cell donors. Results-In vitro, alloreactive CD4 T cells were competent to lyse donor MHC class II+ target cells, largely by a Fas-dependent mechanism. In vivo, the individual disruption of either donor Fas expression (lpr) or CD4 T cell-derived perforin had no signifcant impact on acute rejection. However, FasL-deficient (gld) CD4 T cells demonstrated delayed allograft rejection. Importantly, the simultaneous removal of both donor Fas expression and CD4 T cell perforin completely abrograted acute rejection, despite the persistence of CD4 T cells within the graft. Conclusions-Results demonstrate that the direct rejection of cardiac allografts by CD4 effector T cells requires the alternative contribution of graft Fas expression and T cell perforin expression.

The Journal of Thoracic and Cardiovascular Surgery, 2005

Objective: Complement activation has been shown to play a significant role in ischemia-reperfusio... more Objective: Complement activation has been shown to play a significant role in ischemia-reperfusion injury after lung transplantation. TP-10 (soluble complement receptor 1 inhibitor) inhibits the activation of complement by inactivating C3a and C5a convertases. This was a clinical trial of TP-10 to reduce ischemia-reperfusion injury in lung transplantation. Methods: In a randomized, double-blinded, multicenter, placebo-controlled trial, 59 patients from four lung transplant programs received TP-10 (10 mg/kg, n ϭ 28) or placebo (n ϭ 31) before reperfusion. This dose achieved 90% complement inhibition for 24 hours, and activity had returned toward normal by 72 hours. Results: At 24 hours, 14 of 28 patients in the TP-10 group (50%) were extubated, whereas only 6 of 31 patients in the placebo group (19%) were (P ϭ .01). The total times on the ventilator and in the intensive care unit both tended to be shorter in the TP-10 group, but these differences did not achieve statistical significance. Among patients requiring cardiopulmonary bypass (n ϭ 5 in placebo group and n ϭ 7 in TP-10 group), the mean duration of mechanical ventilation was reduced by 11 days in the TP-10 group (10.6 Ϯ 5.0 days vs 21.5 Ϯ 5.9 days in placebo group, P ϭ .2). Operative deaths, incidences of infection and rejection, and length of hospital stay were not significantly different between the two groups. Conclusions: Short-term complement inhibition with TP-10 led to early extubation in a significantly higher proportion of lung transplant recipients. The effect of TP-10 was greater among patients undergoing cardiopulmonary bypass, with a large reduction in ventilator days. Complement inhibition thus significantly decreases the duration of mechanical ventilation and could be useful in improving the outcome of lung transplant recipients.

The Journal of Thoracic and Cardiovascular Surgery, 2008

Objective: Single-lung transplantation is an accepted treatment for end-stage lung disease caused... more Objective: Single-lung transplantation is an accepted treatment for end-stage lung disease caused by chronic obstructive pulmonary disease. A complication unique to single-lung transplantation for chronic obstructive pulmonary disease is graft dysfunction due to compression caused by native lung hyperinflation. We hypothesized that patients with functional compromise from native lung hyperinflation would benefit from native lung volume reduction surgery. Methods: The charts of all patients undergoing single-lung transplantation for chronic obstructive pulmonary disease were reviewed for lung volume reduction surgery of their native lung. Data regarding length of stay, surgical morbidity and mortality, overall survival, type of lung volume reduction surgery, and pulmonary function were recorded to evaluate the effect of lung volume reduction surgery.

European Respiratory Journal, 2010

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. Th... more The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1a in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n56; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n513; stage III and IV). We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1a and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1a and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1a protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1a protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry. In conclusion, reduced expression of HIF-1a protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.

Clinical Infectious Diseases, 1996

Mycoplasma hominis is a significant pathogen in immunocompromised hosts, particularly organ trans... more Mycoplasma hominis is a significant pathogen in immunocompromised hosts, particularly organ transplant recipients. We describe two recipients of lung allografts from the same donor who had M. hominis pleuropulmonary infection during the immediate postoperative period. The most likely source of infection in these cases was the donor's respiratory tract. The slow-growing pinpoint colonies formed by M. hominis on routine bacterial culture medium may be easily overlooked and should be subcultured to mycoplasmal medium for definitive identification. The recommended management of this infection consists of drainage and antimicrobial therapy with tetracycline, clindamycin, or a fluoroquinolone. This report highlights the potential for M. hominis to be transmitted from donor to recipient during organ transplantation. Mycoplasma hominis is a resident of the genital and respiratory tracts ofhealthy adults [1, 2] and has long been recognized as a urogenital and peripartum pathogen. Its role as an extragenital pathogen in immunocompromised hosts has more recently been appreciated [3]. We present two cases of M. hominis pulmonary infection in recipients of lung allografts from the same donor. These cases suggest the potential for transmission of M hominis from donor to host during solid organ transplantation. Case Reports Case 1 A 65-year-old man received a right-sided lung transplant because of respiratory insufficiency related to a I-antitrypsin deficiency. The donor, a 20-year-old man who had received a gunshot wound to the head, had been intubated for 24 hours; his chest radiograph before organ donation was unremarkable. The recipient received therapy with azathioprine, cyclosporin A, prednisone, ceftazidime, vancomycin, and trimethoprim-su1famethoxazole postoperatively. His clinical course was complicated by hemorrhagic pleural effusion and persistent pneumothorax. On postoperative day 7 fever without respiratory deterioration developed. Physical examination revealed diffuse coarse rhonchi and a pleural friction rub. The peripheral WBC count was 21.1 X 109fL (95% neutrophils). Chest radiography revealed bilateral ill-defined infiltrates. Bacterial cultures of preoperative bronchial specimens from the donor were signifi