Takekazu Iwata

Anti-Type V Collagen Lymphocytes that Express IL-17 and IL-23 Induce Rejection Pathology in Fresh and Well-Healed Lung Transplants

Immunity to collagen V [col(V)] contributes to lung ‘rejection.’ We hypothesized that ischemia reperfusion injury (IRI) associated with lung transplantation unmasks antigenic col(V) such that fresh and well‐healed lung grafts have differential susceptibility to anti‐col(V)‐mediated injury; and expression of the autoimmune cytokines, IL‐17 and IL‐23, are associated with this process. Adoptive transfer of col(V)‐reactive lymphocytes to WKY rats induced grade 2 rejection in fresh isografts, but induced worse pathology (grade 3) when transferred to isograft recipients 30 days post‐transplantation. Immunhistochemistry detected col(V) in fresh and well‐healed isografts but not native lungs. Hen egg lysozyme‐reactive lymphocytes (HEL, control) did not induce lung disease in any group. Col(V), but not HEL, immunization induced transcripts for IL‐17 and IL‐23 (p19) in the cells utilized for adoptive transfer. Transcripts for IL‐17 were upregulated in fresh, but not well‐healed isografts after transfer of col(V)‐reactive cells. These data show that IRI predisposes to anti‐col(V)‐mediated pathology; col(V)‐reactive lymphocytes express IL‐17 and IL‐23; and anti‐col(V)‐mediated lung disease is associated with local expression of IL‐17. Finally, because of similar histologic patterns, the pathology of clinical rejection may reflect the activity of autoimmunity to col(V) and/or alloimmunity.

Anti-type V collagen humoral immunity in lung transplant primary graft dysfunction

Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO2/FiO2, an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-γ, TNF-α, and IL-1β locally; and induced significant reductions in PaO2/FiO2. Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.

Impact of interstitial lung disease on surgical morbidity and mortality for lung cancer: analyses of short-term and long-term outcomes

BACKGROUND This study investigated postoperative morbidity, mortality, and the long-term survival for patients with lung cancer who have interstitial lung diseases. METHODS A retrospective chart review of 931 patients with lung cancer who underwent pulmonary resection at Chiba University Hospital between 1990 and 2000 was undertaken. Interstitial lung disease was defined by medical history, physical examination, and abnormalities compatible with bilateral lung fibrosis on chest computed tomography or high-resolution computed tomography (36 patients: 3.9%, interstitial lung diseases group). The remaining 895 patients (96.1%) were categorized as non-interstitial lung disease group. RESULTS The incidence of postoperative pneumonia and acute or exacerbation of interstitial pneumonia was higher in the interstitial lung disease group (all P <.05). Thirty-day mortality was statistically equivalent between the interstitial lung disease and the non-interstitial lung disease groups (P =.30). The 5-year overall survivals were 62.5% (non-interstitial lung disease) and 35.6% (interstitial lung disease). Respiratory failure was the second main cause of death after the recurrence of primary cancer in the interstitial lung disease group. The risk factors for long-term mortality were interstitial lung diseases, advanced pathologic stage, male sex, high age, and positive smoking history (all P <.05). CONCLUSIONS Interstitial lung disease was a risk factor for developing postoperative morbidity and mortality and poor long-term survival due to the occurrence of respiratory failure.

Minimal alteration of pulmonary function after lobectomy in lung cancer patients with chronic obstructive pulmonary disease.

BACKGROUND The aim of this study was to evaluate the influence of chronic obstructive pulmonary diseases (COPD) on postoperative pulmonary function and to elucidate the factors for decreasing the reduction of pulmonary function after lobectomy. METHODS We conducted a retrospective chart review of 521 patients who had undergone lobectomy for lung cancer at Chiba University Hospital between 1990 and 2000. Forty-eight patients were categorized as COPD, defined as percentage of predicted forced expiratory volume at 1 second (FEV1) less than or equal to 70% and percentage of FEV1 to forced vital capacity less than or equal to 70%. The remaining 473 patients were categorized as non-COPD. RESULTS Although all preoperative pulmonary function test data and arterial oxygen tension were significantly lower in the COPD group, postoperative arterial oxygen tension and FEV1 were equivalent between the two groups, and the ratio of actual postoperative to predicted postoperative FEV1 was significantly better in the COPD group (p < 0.001). With multivariable analysis, COPD and pulmonary resection of the lower portion of the lung (lower or middle-lower lobectomies) were identified as independent factors for the minimal deterioration of FEV1. Actual postoperative FEV1 was 15% lower and higher than predicted, respectively, in the non-COPD patients with upper portion lobectomy and the COPD patients with lower portion lobectomy. Finally, we created a new equation for predicting postoperative FEV1, and it produced a higher coefficient of determination (R(2)) than the conventional one. CONCLUSIONS The postoperative ventilatory function in patients with COPD who had lower or middle-lower lobectomies was better preserved than predicted.

Th-17, Monokines, Collagen Type V, and Primary Graft Dysfunction in Lung Transplantation

RATIONALE The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation. OBJECTIVES To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD. METHODS Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity. MEASUREMENTS AND MAIN RESULTS We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts. CONCLUSIONS The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.

Lung transplant ischemia reperfusion injury: Metalloprotease inhibition down-regulates exposure of type V collagen, growth-related oncogene-induced neutrophil chemotaxis, and tumor necrosis factor-α expression

Background. Immunity to type V collagen [col(V)] contributes to lung transplant rejection. Matrix metalloproteases (MMPs), which are induced by transplant-related ischemia-reperfusion injury (IRI), could expose col(V) and regulate local IRI-induced inflammation. Methods. To test the hypothesis that MMPs induce col(V) exposure and inflammation, Wistar-Kyoto rats were treated with the MMP inhibitor, COL-3, before inducing lung IRI without transplantation, and in parallel studies, Wistar-Kyoto lung donor and recipients were treated with COL-3 pre- and postisograft lung transplantation. Results. Ischemia-reperfusion injury induced growth-related oncogene/CINC-1-dependent neutrophil influx, and up-regulated tumor necrosis factor-α. MMP2 and MMP9, induced at 4 and 24 hr after IRI, respectively, were associated with detection of antigenic col(V) in bronchoalveolar lavage and lung interstitium because of MMP-mediated matrix degradation. MMP-inhibitor treatment significantly reduced polymorphonuclear leukocytes, growth-related oncogene/CINC-1, and tumor necrosis factor-α; abrogated MMP-9 expression; and resulted in lower levels of antigenic col(V) in bronchoalveolar lavage. In the lung transplant model, inhibiting MMPs in the donor before lung harvest and in the recipient after lung transplantation resulted in improved oxygenation and diminished polymorphonuclear leukocyte influx into the isograft. Conclusion. MMP inhibition may be a potential therapy to prevent release of antigenic col(V) and ameliorate IRI in the transplant recipient.

Trends of bacterial colonisation and the risk of postoperative pneumonia in lung cancer patients with chronic obstructive pulmonary disease

BACKGROUND Lung cancer patients with chronic obstructive pulmonary disease (COPD) have a high risk of developing postoperative pneumonia (POP). This study aims to investigate the impact of COPD on POP and the trends for perioperative bronchial colonisation by micro-organisms. METHODS A retrospective chart review was made for 626 patients who underwent lung cancer surgeries at the Chiba University Hospital between 1996 and 2005. The patients were categorised as non-COPD (n=475) and COPD (forced expiratory volume in 1s/forced vital capacity (FEV1/FVC) <70%; n=151). All the patients had sputum and bronchial bacterial cultures examined for potentially pathogenic micro-organisms (PPMs). Risk factors for POP and mortality were analysed. RESULTS Patients with COPD had a significantly higher incidence of POP (23/151, 15.2%) than those without COPD (17/475, 3.6%) (p<0.0001). Preoperative bronchial bacterial examinations showed that 50 of 475 patients without COPD (10.5%) had positive cultures, while the results for 30 of 151 patients with COPD (19.9%) were positive (p=0.0111). Only 31 of 548 patients (5.7%) who did not show any preoperative PPMs had POP, while nine of 78 patients (11.5%) who presented preoperative PPMs had POP (p=0.0469). The PPMs that emerged postoperatively were primarily Staphylococcus aureus (and Gram-negative bacilli (94.4% of PPMs), while they were seen less frequently preoperatively (46.5% of PPMs). Multivariate analysis demonstrated that advanced age and FEV1/FVC were independent risk factors for POP. Patients with POP had significantly worse long-term survivals than those without POP (p=0.0004). CONCLUSION COPD was a risk factor for POP. Staphylococcus aureus and Gram-negative bacilli should be targets for postoperative prophylactic antibiotic selection. Patients with POP had poor long-term survivals.

Pulmonary resection for lung cancer with malignant pleural disease first detected at thoracotomy

OBJECTIVES The prognosis of non-small-cell lung cancer (NSCLC) patients with malignant pleural disease (MPD), characterized by malignant pleural effusion and/or malignant pleural nodules, is reported to be poor, and patients with MPD are generally not subjected to surgery. However, whether or not the primary tumor should be resected, when MPD is first detected at thoracotomy, is controversial. METHODS The clinical records of 1623 consecutive NSCLC patients, who underwent surgery between 1990 and 2007, were retrospectively reviewed. A hundred patients (6.2%) were classified with pathological stage IV disease according to the seventh edition of the Union for International Cancer Control (UICC) staging system. There were 73 patients with MPD, which included 32 with effusion without nodules (MPE) and 41 with nodules with or without effusion (MPN). Intra- or postoperative pleural chemotherapy was administered to 37 MPD patients. RESULTS The median survival time, the 3-year survival rate and the 5-year survival rate for MPD patients were 25.9 months, 41.4%, and 23.7%, respectively, which are better outcomes than those for M1b patients (8.7 months, 18% and 18%, respectively) (log-lank test: p=0.014). Among MPD patients, N0-1 disease was determined to be a favorable prognostic factor (p=0.01). MPD status (MPE or MPN) was not prognostically significant (p=0.40). MPE patients with N0-1 disease had a significantly better prognosis with a 5-year survival rate of 63.6% compared to MPE patients with N2-3 disease (p=0.003). Twenty-seven percent of MPN patients with N0-1 disease achieved 5-year survival, whereas none of the MPD patients with N2-3 disease survived longer than 5 years after surgery. CONCLUSIONS The prognosis of patients with surgically detected MPD, who underwent resection, was better than that of M1b patients. MPE patients with N0-1 disease may be candidates for resection.

Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung.

Background. Upregulation of matrix metalloproteinases (MMPs) has been associated with chronic lung allograft rejection known as bronchiolitis obliterans syndrome. It has been suggested that MMP inhibition could prevent the rejection response. However, the effect of MMP inhibition on lung allograft rejection has not been reported. Methods. Utilizing a rat model of lung transplantation, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were overexpressed by gene therapy in F344 rat lung allografts prior to transplantation into WKY recipient rats. Separately, WKY rats that received F344 lung allografts were treated systemically with COL-3, a global MMP inhibitor. Results. TIMP-1 and TIMP-2 had differential effects on delayed type hypersensitivity (DTH) responses to donor antigens and type V collagen, an autoantigen involved in the rejection response. Neither TIMP-1 or TIMP-2 affected the onset of rejection pathology. COL-3 suppressed DTH responses to donor antigens and type V collagen, abrogated local production of tumor necrosis factor-&agr;, and interleukin-1&bgr;. Although it did not prevent rejection pathology, COL-3 (30 mg/kg) induced intragraft B cell hyperplasia suggestive of posttransplant proliferative disorder (PTLD). Conclusions. These data identify a complex role for MMPs and TIMPs in the immunopathogenesis of lung allograft rejection, and indicate their effects are not limited to matrix remodeling.

Risk factors predictive of atrial fibrillation after lung cancer surgery

Postoperative atrial fibrillation (POAF), the most frequent arrhythmia after pulmonary resection, is a cause of both morbidity and mortality. Being able to predict the risk of POAF before surgery would help us evaluate the surgical risk and plan prophylaxis. We investigated the reported preoperative risk factors associated with the incidence of POAF and found that the recommended predictive factors were quite variable. Therefore, we evaluated the previously reported preoperative risk factors for POAF using our institutional data. We discuss our findings in this short review. Male gender, resected lung volume, brain natriuretic peptide (BNP), and left ventricular early transmitral velocity/mitral annular early diastolic velocity (E/e′) calculated by echocardiography were suggested as independent predictors for POAF, but the predictive values of each individual parameter were not high. The lack of definitive predictors for POAF warrants further investigations by gathering the reported knowledge, to establish an effective preoperative examination strategy.