The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Surgical lung biopsy for the diagnosis of interstitial lung disease: a review of the literature and recommendations for optimizing safety and efficacy.

Making an accurate diagnosis of a specific type of interstitial lung disease (ILD) requires a structured and comprehensive approach that includes a complete patient history, careful physical examination, appropriate laboratory testing, and thoracic imaging. If invasive procedures are required, bronchoscopy with bronchoalveolar lavage (BAL) and/or endoscopic lung biopsy (ELB) can frequently establish a confident diagnosis. However, surgical lung biopsy (SLB) may be required to make a confident diagnosis. Because SLB may be associated with a significant risk of morbidity and mortality, we performed a comprehensive literature review of all available literature published in the English language that reported outcomes of surgical lung biopsy performed for the diagnosis of ILD. The overall 30-day mortality for open lung biopsy (OLB) was 4.3% versus 2.1% for video-assisted thorascopic surgery (VATS) biopsy, and non-lethal complications appeared to occur more frequently with OLB (18.1%) vs. VATS (9.6%) procedures. In addition to presenting the results of our comprehensive literature review on SLB for the diagnosis of ILD, we suggest an approach that minimizes risks to patients and optimizes the diagnostic utility of SLB when SLB must be performed to obtain a confident ILD diagnosis.

Immunohistological pointers to a possible role for excessive cathelicidin (LL-37) expression by apocrine sweat glands in the pathogenesis of hidradenitis suppurativa/acne inversa.

BACKGROUND: The cause of follicular occlusion, a key early event in the pathogenesis of hidradenitis suppurativa (HS), also known as acne inversa, remains unknown. OBJECTIVES: To identify changes, if any, in the antimicrobial peptide (AMP) and cytokine expression profile of HS affected human skin. METHODS: Quantitative immunohistomorphometry was used to compare the in situ protein expression of selected AMPs and cytokines in lesional HS skin from 18 patients with that in healthy skin (n = 12). The lesional skin from patients with HS was histologically subclassified based on the predominance of inflammation vs. scarring. RESULTS: Compared with healthy controls, significantly increased immunoreactivity for cathelicidin (LL-37) was noted in the apocrine sweat gland and distal outer root sheath (ORS) of the hair follicle (HF) epithelium in lesional HS skin. Immunoreactivity for LL-37, psoriasin, human ß-defensin 3 (hBD3), α-melanocyte stimulating hormone (α-MSH), macrophage migration inhibitory factor (MIF), tumour necrosis factor (TNF)-α and interleukin (IL)-8 was significantly increased in HS epidermis. LL-37 and TNF-α immunoreactivity was also increased in the dermis of lesional HS skin. In contrast, lysozyme expression was decreased in the epidermis of lesional HS skin, while that of TNF-α and IL-8 was decreased in the proximal ORS of HFs in HS lesions. These differences were most pronounced in HS with predominant inflammation. CONCLUSIONS: Our observations raise the question as to whether excessive secretion of AMPs by the skin, in particular by the apocrine sweat glands, distal HF epithelium, and epidermis, may attract inflammation and thus facilitate or promote HS development.

Bronchoalveolar lavage for the evaluation of interstitial lung disease: is it clinically useful?

Although the application of thoracic high-resolution computed tomography (HRCT) to clinical pulmonology has revolutionised the diagnostic approach to patients with suspected interstitial lung disease (ILD), additional testing is often needed to make a confident ILD diagnosis. Bronchoalveolar lavage (BAL) can play a significant role in making an accurate and confident diagnosis of specific forms of ILD. When BAL is used in conjunction with comprehensive clinical information and HRCT, BAL nucleated immune cell patterns can frequently provide useful information for diagnostic evaluation and lessen the need to proceed to more invasive procedures, such as surgical lung biopsy. Additionally, BAL can identify confounding conditions, such as infection or malignancy. However, BAL technique, and protocols for processing and analysing BAL fluid are critically important for providing useful information. This perspective reviews the current status of using BAL as a diagnostic tool for the diagnosis of ILD.

Interstitial lung disease in the elderly: pathogenesis, diagnosis and management.

Advancing age is associated with increased risk for some forms of interstitial lung disease (ILD), and this risk is especially reflected by the considerably increased incidence of idiopathic pulmonary fibrosis (IPF) in the elderly. Although the causes of this increased risk are not well-defined, both ageing and IPF have been associated with shortening of telomeres due to telomerase deficiency. Thoracic imaging with high-resolution computed tomographic (HRCT) scanning plays a key role in the diagnosis of ILD in the elderly, and a characteristic appearance of the lung parenchymal changes on HRCT may provide a confident diagnosis and obviate the need for invasive testing such as surgical lung biopsy. An effective treatment for IPF remains elusive, but many patients will benefit from supportive care and treatment of various co-morbid conditions that are often found in patients with IPF.

Does collapse of immune privilege in the hair-follicle bulge play a role in the pathogenesis of primary cicatricial alopecia?

BACKGROUND: The hair-follicle bulge has recently been added to a growing list of human tissue compartments that exhibit a complex combination of immunosuppressive mechanisms, termed immune privilege (IP), which seem to restrict immune-mediated injury in specific locations. As epithelial hair-follicle stem cells (eHFSC) reside in the hair-follicle bulge region, it is conceivable that these IP mechanisms protect this vital compartment from immune-mediated damage, thereby ensuring the ongoing growth and cyclic regeneration of the hair follicle. Primary cicatricial alopecias (PCA) are a group of inflammatory hair disorders that result in hair-follicle destruction and permanent alopecia. Growing evidence suggests that eHFSC destruction is a key factor in the permanent follicle loss seen in these conditions. AIM: To explore the possible role of bulge IP collapse in PCA pathogenesis. METHODS: We report three clinically distinct cases of PCA. Immunohistochemical analyses of paired biopsies from lesional and uninvolved scalp skin were compared using recognized markers of IP. RESULTS: Immunohistochemical investigation found increased expression of major histocompatibility complex (MHC) classes I and II and of beta2-microglobulin in the bulge region of lesional follicles compared with uninvolved follicles in each case. Further, expression of the bulge marker keratin 15 was reduced in lesional skin in two of the cases. CONCLUSIONS: This small series represents our first preliminary attempts to ascertain whether bulge IP collapse may play a role in PCA pathogenesis. We present standard parameters relating to hair-follicle IP in the bulge region of three patients with distinct PCA variants, and show the presence of features consistent with bulge IP collapse in each case.

Predictors of survival in idiopathic interstitial pneumonia.

AIM: To evaluate the ability of newly identified clinical factors to predict prognosis and survival in idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP). METHODS: Seventy-eight patients referred to the University of Genoa and the Regional Hospital of Aosta between January 1995 and December 2006 were evaluated prospectively. Fifty-nine patients were diagnosed with IPF and 19 with NSIP on the basis of surgical lung biopsy specimens. Gender, age at diagnosis, smoking, New York Heart Association class (NYHA), systolic pulmonary artery pressure (sPAP), Octreoscan uptake index (UI), and therapy were the chosen variables. Primary end-point was survival. RESULTS: With the exception of gender and smoking history, all baseline patient characteristics correlated significantly with the diagnosis (IPF vs. NSIP). Median survival for the entire study group was 52.7 months. Univariate analysis showed poorer survival for the IPF group versus the NSIP group, and survival was significantly lower for older patients (p < 0.001). Multivariate analysis confirmed the negative prognostic effect of age (p < 0.001) on survival with a risk of death for older patients ( > OR =66 years old) being more than 4 times higher than that for younger patients (<58 yr.). NYHA class and pulmonary artery pressure were also significant predictors of survival, and all patients with a sPAP < OR = 35-mm Hg were alive at the end of the follow-up period. There was a good correlation between Octreoscan uptake index and the diagnosis. CONCLUSION: Diagnosis (IPF vs. NSIP), NYHA class, sPAP, and especially age appear to represent important prognostic indicators in the two most prevalent forms of idiopathic pulmonary fibrosis (IPF and NSIP). Lower Octreoscan uptake values were found in all patients with IPF, suggesting that this test may have a role as a new predictor of survival for differentiating IPF from NSIP.

The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions.

BACKGROUND: Alpha-melanocyte stimulating hormone (alpha-MSH) is a well-tolerated immunomodulator with cytoprotective and anti-inflammatory effects that is known to stimulate melanogenesis and proliferation of follicular melanocytes. As human hair follicles (HFs) locally synthesize alpha-MSH, pharmacologically more easily handled alpha-MSH-related tripeptides, such as K(D)PT, may imitate this endogenous regulation, and may show a favourable side-effect profile on clinical use. OBJECTIVES: To investigate the effect of the synthetic, alpha-MSH-related peptide K(D)PT [which is identical to interleukin (IL)-1beta(193-195)] on melanogenesis in human anagen HFs, under normal and proinflammatory growth conditions. METHODS: Normal human anagen VI scalp HFs were microdissected and organ cultured with different concentrations of K(D)PT with or without coadministration of a proinflammatory, catagen-inducing stimulus, interferon (INF)-gamma. Masson-Fontana histochemistry and NKI/beteb immunohistochemistry were employed to assess changes in the degree of human HF pigmentation and melanocyte dendricity. RESULTS: As confirmed by quantitative (immuno-)histomorphometry, compared with controls, K(D)PT alone did not affect human HF pigmentation in organ culture. However, in the presence of a strong, prototypic proinflammatory stimulus (IFN-gamma), K(D)PT significantly stimulated HF melanin content and melanocyte dendrite formation in situ. CONCLUSIONS: The IL-1beta- and alpha-MSH-related tripeptide, K(D)PT, displays interesting hair pigmentation-stimulatory activities under proinflammatory conditions. These might become exploitable for innovative antigreying strategies, notably in postinflammatory poliosis (regrowth of white hair, e.g. during recovery from alopecia areata), where no effective clinical therapy is yet available.

Human hair follicle epithelium has an antimicrobial defence system that includes the inducible antimicrobial peptide psoriasin (S100A7) and RNase 7.

BACKGROUND: Hair follicle (HF) ostia represent a potential port of microbial entry into the skin. However, they rarely show clinical signs of infection. This suggests the presence of local, efficient, antimicrobial defence systems, which may include antimicrobial peptides (AMPs). OBJECTIVES: We determined the presence and distribution of the major AMPs, RNase 7 and psoriasin (S100A7), in human scalp HFs. We investigated whether HF production of these AMPs was induced by prototypic microbial products and proinflammatory cytokines, i.e. interferon (IFN)-gamma. Finally, we examined whether the classical pathways for AMP induction, such as toll-like receptor (TLR)4 and TLR5 expression, are present in human HFs and up-regulated after stimulation with bacterium-associated ligands. METHODS: Cryosections from fresh or organ-cultured full-thickness normal human scalp skin treated with lipopolysaccharide (LPS), flagellin, protein A, lipoteichoic acid (LTA) or IFN-gamma were stained for psoriasin and RNase 7 immunoreactivity (IR) as well as for TLR4 and TLR5. In addition, outer root sheath cell culture and semiquantitative analysis of mRNA expression levels of RNase 7 and psoriasin were performed. RESULTS: Specific RNase 7 IR was present throughout the entire HF outer root sheath in situ and in cell culture, whereas psoriasin IR was present only in the most distal compartment and not detectable in cultured ORS cells. Upon treatment with Gram-positive (LTA, protein A) or Gram-negative bacterial (LPS, flagellin) cell wall components, or with the cytokine IFN-gamma, the IR of both psoriasin and RNase 7 was modified. TLR4 and TLR5 IR was detected in the normal HF epithelium and were upregulated after treatment with their respective ligand. The mRNA analysis confirmed the immunohistochemistry results. CONCLUSIONS: This pilot study suggests that normal human scalp HF epithelium possesses a functional antimicrobial defence system, which includes the AMPs RNase 7 and psoriasin, and TLRs, and that these are induced by classical microbial products.

Evidence that the bulge region is a site of relative immune privilege in human hair follicles.

BACKGROUND: Recent gene profiling data suggest that, besides the anagen hair bulb, the epithelial stem cell region in the outer root sheath of hair follicles (HFs), termed the bulge, may also represent an area of relative immune privilege (IP). OBJECTIVES: To investigate whether the human HF bulge is a site of relative IP within anagen VI HFs. METHODS: Anagen VI HFs from normal human scalp skin were analysed using immunohistological staining techniques, quantitative histomorphometry and statistical analysis. For functional evidence we performed full-thickness human scalp skin organ cultures to investigate whether interferon (IFN)-gamma, a key inducer of IP collapse in hair bulbs, has a similar effect on the putative bulge IP. RESULTS: Major histocompatibility complex (MHC) class Ia, beta(2)-microglobulin and MHC class II immunoreactivity are downregulated in the human bulge. The immunosuppressants alpha-melanocyte stimulating hormone, transforming growth factor-beta2, macrophage migration inhibitory factor and indoleamine-2,3-dioxygenase (IDO) are upregulated in the CD200+, stem cell-rich bulge region. These CD200+ cells also co-express HLA-E. Furthermore, IFN-gamma induces significant ectopic MHC class Ia expression in bulge cells of organ-cultured human scalp skin. CONCLUSIONS: These data suggest that the bulge of human anagen HFs represents a hitherto unrecognized site of relative IP in human skin. Simultaneously, we present the first evidence of IDO and HLA-E protein expression in normal human HFs. Bulge IP presumably protects the HF epithelial stem cell reservoir from autoaggressive immune attack whereas a loss of bulge IP may play a central role in the pathogenesis of cicatricial alopecias.

Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis.

BACKGROUND: The consensus statement on the Diagnosis and Therapy of Idiopathic Pulmonary Fibrosis (IPF) formulated by the American Thoracic Society/European Respiratory Society (ATS/ERS) was published in 2000. Acceptance and implementation of these guidelines have not been assessed. We surveyed the fellows of the American College of Chest Physicians (FCCP) to establish current practice patterns regarding the diagnosis and therapy of IPF. METHODS: We electronically distributed a 32-item questionnaire to all 6443 pulmonary medicine board-certified Fellows of the American College of Chest Physicians. The response rate was 13%. Demographic characteristics were similar between respondents and non-respondents. RESULTS: Seventy-two percent of respondents were familiar with the ATS/ERS consensus statement and 63% found it clinically useful. However, a similar number of respondents indicated that an update is needed. Bronchoscopy and surgical lung biopsy are used infrequently. Forty-five percent of pulmonary physicians advocate providing only supportive care for patients outside of clinical trials. If pharmacological therapy is recommended, prednisone (either alone or in combination with azathioprine) or off-label agents are preferentially prescribed. Despite physician awareness (79%) of clinical trials, interested patients are not consistently referred (54%). A majority of respondents (61%) felt that lung transplantation represents the only effective therapy for IPF, and 86% refer their patients to lung transplant centers. CONCLUSIONS: There is substantial variability among pulmonary physicians in the diagnosis and management of IPF. This may, in part, reflect the current lack of effective pharmacologic therapy. Updated practice guidelines are needed for the diagnosis and therapy of IPF.

Lung transplantation for cystic fibrosis: current concepts and one center's experience.

BACKGROUND: Although new approaches to the treatment of patients with cystic fibrosis (CF) are significantly prolonging their lives, most patients will eventually develop respiratory failure due to progressive bronchiectasis caused by chronic lung infection and inflammation and die from to respiratory failure. We examined our center's (University of Wisconsin Hospital and Clinics) experience with lung transplantation for patients with CF and reviewed the literature to examine current and evolving approaches to transplantation for this indication. METHODS: We reviewed all published literature pertaining to lung transplantation for CF through 2006, and we reviewed all aspects of transplantation for patients with CF at our institution from 1994 to 2005. RESULTS: Major complications following lung transplantation include acute rejection, bacterial infection, and bronchiolitis obliterans. Five-year survival at UWHC (Kaplan-Meier) is 67%, and survival was not adversely affected by transplanting patients receiving mechanical ventilation. The major cause of death for transplant recipients was bronchiolitis obliterans syndrome (BOS). CONCLUSIONS: Lung transplantation for CF is associated with acceptable survival rates and can improve quality of life. Lung transplant should be offered to all patients with advanced CF lung disease if they meet currently accepted inclusion and exclusion criteria.

Neutrophils and low-grade inflammation in the seemingly normal aging human lung.

Lung function deteriorates with age and is associated with elastin loss, loss of elastic recoil and decline in diffusing capacity for carbon monoxide. To determine whether increased numbers of neutrophils can be found in the lower respiratory tract in healthy, clinically normal individuals who are more advanced in age, we performed bronchoalveolar lavage (BAL) on individuals in three discontinuous age groups (Group I, 19-36 years; Group II, 45-55 years; Group III, 64 83 years). We found that neutrophils were increased in many individuals in Group III compared to Group I. The neutrophil cell differential count was 1.44+/-0.18% (mean+/-S.E.M.) for Group I versus 3.88+/-0.81% for Group III (P < 0.01) and neutrophils x 10(3)/ml BAL fluid was 1.7+/-0.2 versus 7.2+/-1.7 for Group I versus Group III, respectively (P < 0.01). Similarly, interleukin-8 (IL-8) (8.5+/-1.7 vs 36.8+/-9.4 pg/ml, P < 0.01) and neutrophil elastase (NE) complexed to alpha1-antiprotease (1.2+/-0.1 vs 16.6+/-7.1 ng/ml, P < 0.02) were significantly elevated in the oldest versus youngest age group, although alpha1-antiprotease (582+/-86 vs 1178+/-148 ng/ml, P < 0.01) and elastase inhibitory capacity (EIC) (8.1+/-1.3 vs 17.7+/-1.9 micromol/ml, P < 0.01) were also significantly increased in the oldest age group. This cross-sectional investigation suggests that low-grade inflammation exists in the air spaces of many clinically normal, older individuals.

Stable lung allograft outcome correlates with the presence of intragraft donor-derived leukocytes.

BACKGROUND: The role of bone marrow-derived "passenger" leukocytes in the outcome of solid organ transplantation remains controversial. This study tested the relationship between high levels of donor-derived leukocytes within the transplanted organ and clinical outcome after lung transplantation. METHODS: Sequential bronchoalveolar lavage samples were obtained from human lung allograft recipients. Leukocytes of donor origin in the bronchoalveolar lavage fluid were detected using two-color immunofluorescence, and the results were correlated with multiple clinical parameters. RESULTS: Mean donor leukocyte levels for the first 200 days after transplantation were higher in patients with a good transplantation outcome compared with those patients who lost their grafts due to acute rejection (AR) or developed bronchiolitis obliterans syndrome. The presence of low numbers of donor-derived leukocytes for the first 200 days after transplantation was found to be a significant risk factor for graft loss due to either acute or chronic rejection (P=0.032). Nearly all patients (85%) experienced AR episodes. However, the time to onset of severe AR episodes was significantly longer (P=0.049), and the incidence of these episodes reduced, in patients who maintained high numbers of donor-derived leukocytes for the first 200 days after transplantation. CONCLUSIONS: The presence of high numbers of donor-derived leukocytes, particularly macrophages, in the transplanted lung in the first 200 days after transplantation was associated with stable graft function. Donor-derived leukocytes were reduced or absent in patients with a poor transplantation outcome. These findings rule out a negative influence of persisting donor leukocytes and are consistent with the emerging two-way models of transplant tolerance.

Soluble HLA class I in epithelial lining fluid of lung transplants: associations with graft outcome.

We hypothesized that the small amounts of donor HLA-A and HLA-B proteins detected in the serum during organ allograft rejection are indicative of higher local releases within the graft itself. We determined the concentrations of total HLA class I (HLA-I) and, in selected cases, specific donor and host HLA-A and HLA-B proteins, in the epithelial lining fluid (ELF) sampled by bronchoalveolar lavage (BAL) of lung transplant recipients (n = 37) and of normal controls (n = 25). We found that 1) HLA-I proteins were enriched in the lung ELF relative to other proteins; 2) the concentration of HLA-I in the ELF of well-functioning transplants was similar to that in normal lungs; 3) HLA-I proteins and total proteins were elevated in the ELF of patients who developed chronic rejection or refractory acute rejection; 4) the concentration of HLA-I was correlated with the percentage of neutrophils but not with the percentage of lymphocytes in the ELF of transplanted lungs; and 5) only the percentage of lymphocytes was elevated in the ELF of transplant patients with active CMV infections. Total HLA-I from the ELF was found to contain a mixture of both donor- and recipient-type HLA-A and HLA-B proteins and the donor-type HLA-A2 was found to be highly enriched in the ELF relative to serum.

Soluble donor HLA class I and beta 2m-free heavy chain in serum of lung transplant recipients: steady-state levels and increases in patients with recurrent CMV infection, acute rejection episodes, and poor outcome.

We determined the concentration of donor sHLA/beta(2)m and total beta(2)m-free heavy chain (HC) in the serum of lung transplant recipients with ELISA assays. While we were unable to detect specific donor beta(2)m-free HCs due to a lack of available antibodies, we could determine if events that led to an increase in the release of beta(2)m-free HC also led to an increase in the release of donor sHLA/beta(2)m, particularly the 36 kDa, proteolytically cleaved form. We found that lung transplants constituitively release donor sHLA/beta(2)m at ng/ml levels. The levels (both of donor sHLA/beta(2)m and total beta(2)m-free HC) were significantly increased in CMV-sero-negative recipients (but not in CMV-sero-positive recipients) at the onset of post-transplant CMV disease. Acute rejection episodes were also associated with an increased release of donor sHLA/beta(2)m, but not of beta(2)m-free HC. However, in patients with particularly poor outcome (i.e., graft loss within 1 year) there was a significant release of beta(2)m-free HC. Analysis of one such patient showed a predominance of 36 kDa forms of donor-sHLA/beta(2)m. Our data are consistent with the hypothesis that the metalloproteinase that cleaves beta(2)m-free HC is active during uncontrolled CMV infection and acute rejection. However, recall responses to CMV and controlled immune responses to donor may result in little or no activation of sHLA class I release.

The therapeutic potential of nitric oxide in lung transplantation.

Endogenously produced oxides of nitrogen appear to play important roles in tissue and organ homeostasis. Endogenous production of nitric oxide, which can be altered in response to various stimuli, can modulate vascular tone, oxyradical cascades, cell adhesion, and other aspects of inflammation. Because exogenously administered (inhaled) nitric oxide can mediate pulmonary vasodilatation and improve pulmonary function in some patients with lung injury, treatment of lung allograft recipients with inhaled nitric oxide may ameliorate ischemia-reperfusion injury, thereby improving perioperative pulmonary function and diminishing ventilatory support requirements. This review examines the biology of nitric oxide and present data that support its potential therapeutic effects for lung transplant recipients.