Single lung transplantation in primates. Modified Stanford heart-lung transplantation technique

Unilateral (left) lung allotransplantation was performed on six monkeys (Macaca fascicularis). Intravenous infusion of prostaglandin E-1 into the donor and cooling of the graft by perfusing the pulmonary artery with modified Euro-Collins solution were used for lung preservation. All six primates survived the operation, with good graft function, and were extubated after 4-6 hours. Mild pulmonary densities were found in all of them 3 days postoperatively. Two monkeys died, after 7 and 16 days, due to allograft failure. Autopsy in both cases showed bronchial stenosis, despite omental wrapping around the anastomosis. No other technical problems arose in the early postoperative course. It is concluded that prostaglandin E-1 pretreatment of the donor and single crystalloid flush of the donor lung improves the function of a single lung graft as well as that of a heart-lung transplant.     

Retrograde flush following topical cooling is superior to preserve the non-heart-beating donor lung

Objective: The use of non-heart-beating donors (NHBD) has been propagated as an alternative to overcome the scarcity of pulmonary grafts. Formation of microthrombi after circulatory arrest, however, is a major concern for the development of reperfusion injury. We looked at the effect and the best route of pulmonary flush following topical cooling in NHBD. Methods: Non-heparinized pigs were sacrificed by ventricular fibrillation and divided into three groups (n = 6 per group). After 1 h of in situ warm ischaemia and 2.5 h of topical cooling, lungs in group I were retrieved unflushed (NF). In group II, lungs were explanted following an anterograde flush (AF) through the pulmonary artery with 50 ml/kg Perfadex^® (6 °C). Finally, in group III, lungs were retrieved after an identical but retrograde flush (RF) via the left atrium. Flush effluent was sampled at intervals to measure haemoglobin concentration. Performance of the left lung was assessed during 60 min in our ex vivo reperfusion model. Wet-to-dry weight ratio (W/D) of both lungs was calculated as an index of pulmonary oedema. IL-1ß and TNF- protein levels in bronchial lavage fluid from both lungs were compared between groups. Results: Haemoglobin concentration (g/dl) was higher in the first effluent in RF versus AF (3.4 ± 1.1 vs 0.6 ± 0.1; p < 0.05). Pulmonary vascular resistance (dynes × s × cm⁻⁵) was 975 ± 85 RF versus 1567 ± 98 AF and 1576 ± 88 NF at 60 min of reperfusion (p < 0.001). Oxygenation (mmHg) and compliance (ml/cmH₂O) were higher (491 ± 44 vs 472 ± 61 and 430 ± 33 NS, 22 ± 3 vs 19 ± 3 and 14 ± 1 NS, respectively) and plateau airway pressure (cmH₂O) was lower (11 ± 1 vs 13 ± 1 and 13 ± 1 NS) after RF versus AF and NF, respectively. No differences in cytokine levels or in W/D ratios were observed between groups after reperfusion. Histology demonstrated microthrombi more often present after AF and NF compared to RF. Conclusion: Retrograde flush of the lung following topical cooling in the NHBD results in a better washout of residual blood and microthrombi and subsequent reduced pulmonary vascular resistance upon reperfusion.     

肺叶、肺段淋巴结引流的解剖学特征

目的探讨肺叶、肺段淋巴结引流的解剖学特征。 方法对9具成人尸体采用解剖乳胶填充剂行胸部淋巴结灌注,然后游离标本的纵隔前、纵隔后及中纵隔淋巴结,同时游离并清扫右肺上、中、下肺叶和各个肺段,以及左肺上、下肺叶和各个肺段的肺内淋巴结、肺门淋巴结;观察淋巴结的分布、数目和淋巴回流状况。 结果在标本上共观察到212个纵隔淋巴结,平均每例23.5个;各区淋巴结的数目以隆突下淋巴结7区和右下气管旁4R最多,其次为右气管支气管旁(10R)、左支气管旁(10L)和主-肺动脉窗区(5区)淋巴结;纵隔各区以隆突下区(7区)淋巴结最大,其次是右气管支气管旁(10R)淋巴结,气管旁淋巴结自上而下直至隆突下淋巴结逐渐增大,并且右侧大于左侧,即下大于上,右大于左。左肺和右肺的肺内淋巴结一般按照亚段淋巴结→段淋巴结→叶淋巴结→叶间淋巴结/肺门淋巴结;右肺上叶、中叶及肺门淋巴结通常回流至上纵隔淋巴结及隆突下淋巴结,下叶回流至下纵隔淋巴结。而左肺上叶一般引流至主—肺动脉窗区淋巴结及隆突下淋巴结,下叶也引流至下纵隔淋巴结。 结论肺叶及纵隔淋巴回流具有一定的规律性,从而为肺叶特异性/系统性淋巴结清扫方式的选择提供了解剖学依据。     

Surfactant function in lung transplantation after 24 hours of ischemia: advantage of retrograde flush perfusion for preservation.

OBJECTIVE: Surfactant function was shown to be impaired in clinical and experimental lung transplantation. This study was designed to define the impact of retrograde flush perfusion on graft and surfactant function after an extended period of ischemia. METHODS: Left lung transplantation was performed after 24 hours of graft ischemia in 12 pigs. In half of the grafts antegrade cold flush perfusion (Perfadex) was used for preservation. In the second group grafts were flushed in a retrograde fashion via the left atrium. Graft function was monitored for 7 hours after transplantation. Before transplantation (basal) and after 2 hours of reperfusion, bronchoalveolar lavage fluid was obtained. Minimal surface tension of bronchoalveolar lavage fluid was determined and the ratio of small and large surfactant aggregates was calculated. Lung water content was analyzed online in the reperfusion period. RESULTS: Right-sided heart failure developed in 2 animals of group 1 (antegrade perfusion) within 2 and 4.5 hours of reperfusion, respectively. All other pigs survived the observation period. PO(2)/FIO(2) (P =.001) and dynamic lung compliance (P =.001) were superior in retrogradely flushed grafts. A comparable increase of minimal surface tension was found after reperfusion in both groups. Small/large surfactant aggregate ratio after reperfusion (P =.03), as well as extravascular lung water content, was higher in the antegrade perfusion group. CONCLUSION: Retrograde flush perfusion for 24-hour lung preservation with low-potassium dextran (Perfadex) solution led to better initial graft function than the standard antegrade perfusion technique. A moderate impairment of surfactant function was found in both groups, which was more pronounced in the antegrade perfusion group.     

Normothermic ex vivo lung perfusion of non-heart-beating donor lungs in pigs: from pretransplant function analysis towards a 6-h machine preservation

Donor shortage urges optimal use of all lungs available. Ex vivo lung perfusion (EVLP) is a method to evaluate lung function before implantation. EVLP was performed in pigs to evaluate lung function, using two different clinical non-heart-beating (NHS) donor protocols: flush perfusion and topical cooling after 1-h warm ischaemia (n = 5 each). Secondly, we investigated whether EVLP can be used for 6 h ex vivo machine preservation (n = 4). In comparison with topical cooling, flush perfusion preserved lung function better during EVLP. During 6 h normothermic EVLP, gas exchange remained stable; however, the pulmonary artery pressure and ventilation pressure showed a significant increase. EVLP is a reliable method for evaluation of lung graft function. Flush perfusion with Perfadex is preferred above topical cooling in NHB lung donation. Six-hour normothermic EVLP is feasible but should be further improved to make ex vivo machine preservation or treatment of lung grafts successful.     

Improved lung function by means of retrograde flush in canine lung transplantation with non-heart-beating donors

OBJECTIVE: Use of lungs from non-heart-beating donors would increase the pulmonary donor pool. The aim of this study was to evaluate the effects of retrograde flush in canine lung transplantation from non-heart-beating donors. METHODS: Left lung transplantation was performed in 12 weight-matched pairs of dogs. Donors were killed without heparinization, left at room temperature for 2 hours, and then randomized into 2 groups. In group AF (n = 6) lung retrieval was performed after flushing the lung block with low potassium dextran glucose (50 mL/kg) solution through the pulmonary artery. In group AF+RF (n = 6) additional retrograde flushing (low potassium dextran glucose, 25 mL/kg) was performed through the left atrium before retrieval. Flushed solution was sampled at intervals to measure hemoglobin concentrations. The lungs were preserved at 4 degrees C for 2 hours, and the left lung was implanted to the recipient being subjected to a total ischemic time of 5 hours. After left lung transplantation, the right pulmonary artery and main bronchus were ligated. Lung function, including arterial blood gas and pulmonary hemodynamics, was measured for 3 hours. For lung function study, statistical analyses were performed by using 1-way analysis of variance with repeated measures. RESULTS: Group AF+RF had significantly better gas exchange and lower wet/dry weight ratio of the transplanted lung than group AF. Changes of hemoglobin concentration in the flushed solution indicated that additional retrograde flush could remove residual microthrombi after antegrade flush. CONCLUSIONS: This study supports the theory that additional retrograde flush improves lung function after lung transplantation by removing residual pulmonary microthrombi in the lungs of non-heart-beating donors.     

In-situ topical cooling of lung grafts: early graft function and surfactant analysis in a porcine single lung transplant model.

OBJECTIVE: Improvement of organ preservation is essential to facilitate acceptance of marginal donor lungs for transplantation. Thus, recruiting non-heart-beating donors (NHBD) may be one reasonable strategy to augment the organ-pool especially in the field of pulmonary transplantation. Topical cooling (TC) of donor lungs could provide fast organ-protection and is an available procedure even in smaller centers. In this study transplanted lung function and surfactant activity in same lungs, which were preserved by TC, were assessed following transplantation. METHODS: Twelve porcine allogeneic single lung transplants were performed. Six lungs that were flush preserved through the antegrade route served as controls. The other six lungs were preserved by TC for 30 min after induction of cardiac arrest by repeated application of cold saline (8 degrees C) to both pleural cavities. Lungs of both groups were stored in LPD solution for 24 h at 8 degrees C. After transplantation, the recipient's right bronchus and right pulmonary artery were clamped. Major endpoints included early graft function over a period of 7 h. Hemodynamic measures and respiratory functions were recorded in 30-min intervals. Surfactant function was determined before transplantation and 2 h after reperfusion by broncho-alveolar lavage fluid analysis. RESULTS: Only four animals of the control-group survived the 7 h reperfusion period. Right heart failure occurred in two animals after 150 and 240 min of reperfusion. All six animals in the TC group survived the observation period. Pulmonary vascular resistance (p<0.01), pulmonary artery pressure (p=0.03), and lung tissue water content remained significantly lower in topically cooled allografts (p=0.01) vs. controls. Surfactant function after transplantation was comparable in both groups with a trend towards lower protein contents (p=0.07) in the broncho-alveolar fluid of grafts after TC. CONCLUSIONS: In-situ TC seems to be a reliable strategy to preserve lungs for up to 24 h. It even surpasses the results of LPD-perfused grafts in hemodynamic function and survival time.     

Antegrade versus retrograde perfusion of the donor lung: impact on the early reperfusion phase

Transpulmonary thermodilution was used to evaluate the effect of flush route during harvest on hemodynamic and respiratory function of the pulmonary graft in the early post-transplant phase. Single lung transplantation was performed in two piglet groups after 24 h of cold storage. Donor organs for group A underwent antegrade perfusion, and those for group R retrograde perfusion. PaO₂, compliance (C), airway resistance (R), extravascular lung water index (EVLWI), pulmonary blood volume index (PBVI), intrathoracic blood volume index (ITBVI), capillary leak (CL), and cardiac function index (CFI) were assessed by transpulmonary thermodilution at baseline, 1, 3, and 6 h after reperfusion. EVLWI was significantly lower in group R. Compliance and PaO₂ were higher in the same group. The two groups did not differ significantly with regard to CFI, PBVI, ITBVI, and airway resistance. Retrograde perfusion of the donor lung had a positive impact on graft function during early reperfusion. Transpulmonary hemodynamic monitoring can be a powerful tool for intra- and postoperative management of transplant patients.     

Restoration of bronchial artery circulation after canine lung allotransplantation.

To evaluate the re-establishment of the bronchial circulation in lung transplantation, we studied 10 immunosuppressed dogs up to 14 weeks after left lung allografting. Selective in vivo bronchial arteriograms were performed repetitively via the transfemoral route. In the early postoperative period, no fillinf og vessels distal of the bronchial anastomosis could be shown. After 12 days, however, continuity of the bronchial arteries across the anastomosis was present, and dye-filled ramifications of these vessels were visualized on the secondary and tertiary bronchi. Reconstitution of the bronchial circulation was also confirmed by postmortem studies after injecting the isolated descending thorasis aorta with colored radiopaque material (microfil). The bronchial mucosa at autopsy was examined microscopically. There was no correlation between its viability and bronchial artery regeneration. Although early ischemia of the transplant bronchus may be after a factor in the bronchial complcations that follow lung transplantation, the present study indicates that this ischemia is not due to failure of bronchial artery regeneration.     

Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E1 infusion.

Improved techniques of pulmonary preservation would help alleviate the critical shortage of donor organs in lung transplantation and would improve early graft function. A previous study demonstrated that cold pulmonary artery flush with low-potassium dextran solution was superior to Euro-Collins solution in preservation of canine lung allografts stored for 12 hours when no pulmonary vasodilator was used before donor lung flush. The present study was designed to determine whether donor pretreatment with prostaglandin E1 would affect the superiority of low-potassium dextran as a preservation solution. Prostaglandin E1 was infused (50 micrograms/min) in 12 donor dogs until potent vasodilation was demonstrated. Low-pressure pulmonary artery flush (50 ml/kg) with either Euro-Collins or low-potassium dextran solution (n = 6 for each group) was performed at 4 degrees C in a randomized, blinded fashion. Heart-lung blocks were extracted and stored at 4 degrees C for 18 hours before left lung allografting. Inflatable cuffs were placed around each pulmonary artery, allowing independent study of the native and transplanted lungs. All 12 recipient dogs survived the 3-day assessment period. Lungs flushed and stored in Euro-Collins or low-potassium dextran solution provided equivalent gas exchange function on day 0 (arterial oxygen tension: Euro-Collins 289 +/- 105 mm Hg versus low-potassium dextran 265 +/- 111 mm Hg; mean +/- standard error of the mean) and on day 3 (Euro-Collins 516 +/- 45 mm Hg versus low-potassium dextran 354 +/- 77 mm Hg; p = 0.10). Mean pulmonary artery pressures in the transplanted lung were not significantly different in the Euro-Collins and low-potassium dextran groups on day 0 (21.4 +/- 2 mm Hg versus 33.7 +/- 5 mm Hg, respectively; p = 0.09) or on day 3 (20.2 +/- 2.7 mm Hg versus 24.2 +/- 5.1 mm Hg, respectively; p = 0.50). We conclude that there was no advantage of low-potassium dextran over Euro-Collins as a flush solution in this 18-hour canine single lung allograft model in which prostaglandin E1 was administered before pulmonary artery flush.     

经肺动脉与支气管动脉血管造影的CTA观察原发肺癌的血供

目的用支气管动脉(BA)和肺动脉(PA)造影CTA观察肺癌血供情况。方法前瞻性观察6例支气管肺癌患者,分别行体循环动脉和肺动脉数字减影血管造影(DSA)后,留置BA导管与PA导管行CTBA与CTPA,观察BA与PA对肺癌的血供。结果CTPA上,无体动脉与左心强化的图像上肿瘤未见强化,有体动脉或左心强化的图像上见肿瘤边缘强化,CT强化值为10.0~45.6 Hu。CTBA上肿瘤部分明显强化,CT强化值为150.3~320.7 Hu,可见杂乱无章的肿瘤血管影,3例见纵隔淋巴结强化。结论本组病例观察表明原发性肺癌由BA为主的多发体循环动脉供血,未发现PA参与供血。     

Contribution of the bronchial circulation to lung preservation

Short preservation time still severely limits lung transplantation. To determine the effect of bronchial arterial flush preservation, we studied 54 dogs using the isolated perfused working lung model. After baseline measurements, lungs were flushed with lactated Ringer's solution (60 ml/kg at 8 degrees C) by one of three methods: pulmonary artery perfusion, bronchial artery perfusion through a 15 cm closed aortic segment, or simultaneous pulmonary-bronchial artery perfusion. These groups were further subdivided and tested after 0, 4, and 17 hours of storage at 4 degrees C (n = 6 each). Lungs were ventilated (flow rate 140 ml/kg/min; inspired oxygen fraction 0.21) and continuously reperfused with normothermic deoxygenated autologous blood in a closed loop. Measured variables were hemodynamics, aerodynamics, and leukocytes in bronchoalveolar lavage. Survival time was determined from initial reperfusion to failure of the lung to oxygenate. After 0 and 4 hours of storage, there was no significant difference in survival times. After 17 hours, lungs subjected to pulmonary-bronchial artery perfusion survived longer than those perfused via either the pulmonary or bronchial arteries alone (120 +/- 24 versus 38 +/- 14 or 52 +/- 16 minutes; p less than 0.01). Pulmonary artery pressure and resistance in all groups except at failure were never different from baseline values in the intact animal. Shunts in the pulmonary-bronchial artery perfusion groups were closest to baseline at onset (8% +/- 4%) and remained lower throughout reperfusion than in the groups subjected to pulmonary or bronchial artery perfusion alone. After 17 hours, static compliance of pulmonary artery-perfused lungs was worse than baseline (1.1 +/- 0.2 x 10(-2) versus 3.2 +/- 0.7 x 10(-2) L/cm H2O/sec; p less than 0.05), whereas compliance in the pulmonary-bronchial artery perfusion groups remained constant (3.6 +/- 1.5 x 10(-2) L/cm H2O/sec). Elastic work performed by lungs subjected to pulmonary-bronchial artery flushing at onset was significantly lower when these lungs were reperfused immediately (201 +/- 14 versus 295 +/- 35 gm-m/min for pulmonary artery-flushed lungs) or after 4 hours of storage (229 +/- 30 versus 290 +/- 24 gm-m/min for pulmonary artery-flushed lungs). Bronchoalveolar lavage after 17 hours in the group subjected to pulmonary bronchial artery flushing demonstrated leukocyte counts similar to those of intact lungs (45 +/- 5 versus 29 +/- 8/mm3) and significantly less than in lungs subjected to pulmonary or bronchial artery flushing (137 +/- 18 or 82 +/- 10/mm3, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)     

Successful retrieval and function of lungs from non-heart-beating donors

BACKGROUND: Lung transplantation has been used effectively as a therapeutic tool in end-stage pulmonary diseases, but organ shortages have restricted its use. There is growing interest in alternative organ sources such as organs from circulation-arrested cadavers, so called non-heart-beating donors. METHODS: We examined the effects of postmortem rapid in situ cadaver lung cooling by bilateral chest cavity flushing (group 2) and by pulmonary artery flush through right heart catheterization followed by pleural cavity flushing (group 3) on pulmonary function and morphology in a rabbit non-heart-beating donor model. The results were compared with those in a control group of heart-beating donors (group 1). RESULTS: At the end of a 2-hour reperfusion period, there were no significant differences in mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary compliance, arteriovenous oxygen, pulmonary wet to dry weight ratio, and lung morphology between the three groups. CONCLUSIONS: Our study demonstrates that using bilateral chest cavity flushing with or without pulmonary flush protects the function and morphology of cadaver lungs and renders them suitable for lung transplantation.     

双血供CT灌注用于肺部疾病研究进展

双血供CT灌注(DI-CTP)可同时定量评估肺动脉(PA)和支气管动脉(BA)供血,显示病理状态下二者供血比例变化,提供肺部病灶形态学和血流动力学信息,有助于鉴别良、恶性病变。本文就DI-CTP用于肺部疾病研究进展进行综述。     

阻断炎症介质的信号转导对极限肝切除术后大鼠肝内细胞因子表达的影响

目的 探讨炎症介质特异性阻断剂AG490对极限肝切除术后大鼠细胞因子信号转导及肝内细胞因子表达的影响。方法 将90％肝切除大鼠38只分为对照组(n=10)和AG490组(n=28),后术中至术后36h内每12h腹腔内注射AG490(1mg／kg),其间检测肝组织中磷酸化Janus激酶2(Jak2)和信号转导与转录激活子3(Stat3)蛋白水平,并测定剩余肝中白细胞介素6(IL-6)和白细胞介素10(IL-10)的表达。结果 应用AG490后,术后8h和12h细胞因子信号蛋白Jak2和Stat3磷酸化显下降并递次改变,大鼠肝脏中IL-6表达、IL-6／IL-10比值下降,而IL-10的表达增高。结论 阻断Jak2与Stat3细胞因子信号通路能使剩余肝内促炎细胞因子表达下降和抗炎细胞因子表达升高,减轻极限肝切除术后大鼠体内炎症反应。     

Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors

Background

Certain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection episodes or graft outcomes. We sought to evaluate the relationships between gene polymorphisms and acute rejection episodes (RG, n = 19) versus stable graft function (NRG, n = 71) in transplant recipients compared with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. Using polymerase chain reaction sequence-specific primers with the Heidelberg kit we genotyped 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes.

Results

Interleukin (IL)-2 TT/GT haplotype was found in 36.8% of RG patients and 6.7% of HCG but not among the NRG (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and nine HCG patients (P = .007); the IL-2 GG/GG haplotype, 18.7% HCG and 4.2% NRG patients (P = .0033); and the IL-2 TT/TT haplotype, five NRG and eight HCG patients, but none of the RG cohort (P > .05). The transforming-growth factor-beta 1 CG/CC haplotype was noted in 15 NRG (21.1%) and four HCG but no RG patients (P < .0001). The IL-2 +166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 −330 GG genotype was demonstrated in 32 healthy controls and three nonrejection transplant patients (P = .0007). Significant differences were concluded between NRG and HCG for IL-6 565 AG, IL-1beta −511 TT and +3962 CC/CT/TT genotypes.

Discussion

We observed significant differences among the frequencies of IL-2 gene polymorphisms among RG and NRG subjects, which agreed with previous clinical, but not in vitro studies.     

Cases of residual tumor at the surgical margin after resection of lung cancer]

Sixty-one cases of primary lung cancer with residual cancer at the surgical margin were studied. The tumor remained at the bronchial stump in 27 cases, in the pleura in 18 cases, in the pulmonary artery or vein in 7 cases, the chest wall in 5 cases, adjacent organs in 5 cases and in the lung in 3 cases. The median survival time (MST) of the surgical margin-positive cases was 17 months and the 5-year survival rate was 24.1%. On the other hand, the MST of surgical margin-negative cases in the same period was 62 months and the 5-year survival rate was 50.7%. The poorer prognosis of the surgical margin-positive cases was statistically significant and this factor was related to the poor prognosis of stage I and II SMP cases. In stage IIIA and stage IIIB cases, the MST of the radiotherapy group was shorter than that of the non-radiotherapy group. The difference concerning prognosis between the bronchial margin-positive cases and other positive cases was not significant. Long survival cases consisted of squamous cell carcinomas with negative lymph nodes in which the residual sites were the bronchial mucosa or parietal pleura. Radiotherapy appeared useful for these cases.     

Effect of ablated airway blood flow on systemic and pulmonary microvascular permeability after smoke inhalation in sheep

The bronchial circulation plays a significant role in the pathogenesis of smoke inhalation. We investigated the physiological manifestations in both the systemic and the pulmonary circulation after smoke inhalation injury, and determined whether ablation of the bronchial circulation had any effect on these changes. We used a chronically instrumented ovine model with lung and prefemoral lymph fistulae to determine the changes in pulmonary and systemic microvascular permeability. Fourteen animals were divided into two groups. The injection group had bronchial circulation ablation with an ethanol injection into the bronchial artery, whereas it was left intact in the sham group. The sham group showed a four-fold increase in lung lymph flow (l-Q(L)) and a two-fold increase in prefemoral lymph flow (s-Q(L)) 24 h after injury. The increase in s-Q(L) was associated with a decrease in lymph oncotic pressure. Therefore, systemic colloid clearance (s-CC), an indicator of systemic microvascular permeability to protein, was unchanged. The ablated bronchial circulation reversed the pulmonary but not the systemic manifestations after smoke inhalation. In conclusion, the pathophysiological events occurring after smoke inhalation were confined to the lung with increased bronchial blood flow delivering inflammatory mediators directly to the lung parenchyma.