Characteristics of neutralizing antibody titers of the SARS-CoV-2 vaccine in maintenance hemodialysis patients.

AIMS: Hemodialysis patients have high COVID-19 severity and mortality rates. For this high-risk group of hemodialysis patients with SARS-CoV-2 infection, early SARS-CoV-2 vaccination is recommended to prevent infection and severe disease. Thus far, few reports have evaluated COVID-19 antibody titers in hemodialysis patients. In this study, we investigated the time course of antibody titers acquired by vaccination in patients on dialysis. MATERIALS AND METHODS: The anti-SARS-CoV-2 spike protein S1 IgG (anti-SP-IgG) antibody titers were compared between 33 outpatient maintenance hemodialysis patients and 32 age- and sex-matched healthy subjects. Antibody tests were performed at five time points: 6 months after the 2nd vaccination, immediately before the 3rd vaccination (8 months after the 2nd vaccination), and 2 weeks, 1 month, and 3 months after the 3rd vaccination. RESULTS: The dialysis patient group had significantly lower values of anti-SP-IgG antibody titers than the control group 6 months after the 2nd vaccination (433.7 ± 36.24 vs. 650.2 (427.2 - 759.4) (AU/mL), p = 0.006) and immediately before the 3rd vaccination (219.3 (129.4 - 423.4) vs. 443.3 (267.1 - 600.4) (AU/mL), p = 0.034), but no significant differences were observed after the 3rd vaccination (19,000.0 (11,000.0 - 3,6000.0) vs. 23,500.0 (20,250.0 - 29,000.0) (AU/mL), p = 0.538). CONCLUSION: This study confirmed that patients undergoing hemodialysis were proven to have acquired sufficient antibody titers after the vaccination.

＜Editors' Choice＞ Effects of exosomes derived from the induced pluripotent stem cells on skin wound healing.

Recently, the effects of stem cell supernatants or exosomes, such as skin wounds, have attracted attention. However, the effects of the induced pluripotent stem (iPS) cell-derived exosomes (iPS-Exos) have not been investigated in detail. Here, we investigated the effects of iPS-Exos on skin wound healing using an animal model. We isolated iPS-Exos from the iPS cell culture media. Control exosomes were isolated from unused iPS cell culture media (M-Exos). We first observed the morphologic characteristics of the isolated exosomes and examined the expression of surface antigens. The effects of these exosomes on the migratory response and proliferation of fibroblasts were analyzed as well. Additionally, using a diabetic ulcer model, the effects of iPS-Exos and M-Exos on skin wound healing were investigated. Transmission electron microscope analysis demonstrated that the size of iPS-Exos (120 ± 25 nm) was significantly larger than that of M-Exos (≤ 100 nm). Flow cytometry analyses showed that iPS-Exos were positive for CD9, CD63, and CD81, whereas they were negative for HLA-ABC and -DR expression. The migratory ability of fibroblasts cocultured with iPS-Exos was shown to be higher than that of the cells cocultured with M-Exos, as demonstrated using scratch assay. Skin wound healing model results showed that the administration of iPS-Exos results in a faster wound closure compared with that observed in the M-Exo group. In conclusion, the results obtained here indicate that iPS-Exos may promote the migration of fibroblasts in vitro and in vivo, suggesting the possibility of using iPS-Exos for the treatment of diabetic ulcer.

Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan.

OBJECTIVE: Persistent cough is a frequent cause of doctor and hospital visits, and its incidence may be increasing. However, diagnosis of the cause of cough remains difficult. Because different causes of cough have different treatments, accurate diagnosis of the cause of cough is critical. To gain a better understanding of the causes of cough in Japan, we performed a multicenter epidemiological study of Japanese patients. METHODS: The study involved seven institutions in five different areas of Japan, and was conducted over 1 year from March 2009. Patients aged ≥16 years attending the participating centers for the first time complaining of cough persisting for ≥3 weeks were eligible. Patients with chest X-ray abnormalities responsible for cough, fever or blood-stained sputum were excluded, while those with wheeze or shortness of breath were included. Frequency and severity of cough were assessed using questionnaires, and laboratory tests were performed to enable differential diagnoses. RESULTS: Among the 313 patients evaluated, mean duration of cough symptoms was 192.1 ± 558.4 days. Cough variant asthma (CVA) was the most common cause of prolonged/chronic cough (42.2%), followed by cough-predominant asthma (CPA) (28.4%), atopic cough (7.3%) and chronic obstructive pulmonary disease (6.7%). Patients with an unclear diagnosis were treated with tulobuterol, a transdermal ß2-agonist preparation, for 1-2 weeks. Transdermal tulobuterol improved assessments of cough in patients with CVA or CPA, enabling rapid diagnosis of these diseases. CONCLUSIONS: These findings show that CVA and CPA are the main causes of cough persisting for ≥3 weeks.

Space Charge Characteristics and Breakdown Properties of Nanostructured SiO2/PP Composites.

Polypropylene (PP) has gained attention in the industry as an environmentally friendly material. However, its electrical properties are compromised due to space charge accumulation during operation, limiting its application in high-voltage DC cable insulation. This study investigates the effect and mechanism of SiO2 with a DDS surface hydrophobic treatment on space charge suppression and the electrical properties of PP composites. The PP matrix was doped with SiO2 nanostructures, both with a DDS surface hydrophobic treatment and untreated as a control group. The functional group structure and dispersion of nanostructured SiO2 in the matrix were characterized. The findings reveal that the incorporation of SiO2 nanostructures effectively mitigates charge accumulation in PP composites. However, a high concentration of unsurfaced nanostructures tends to agglomerate, resulting in inadequate space charge suppression and a diminished DC breakdown field strength. Nonetheless, surface treatment improves the dispersion of SiO2 within the matrix. Notably, the composite containing 1.0 wt% of surface hydrophobic SiO2 exhibits the least space charge accumulation. Compared to the base material PP, the average charge density is reduced by 83.9% after the 1800 s short-circuit discharges. Moreover, its DC breakdown field strength reaches 3.45 × 108 V/m, surpassing pure PP by 19.4% and untreated SiO2/PP composites of the same proportion by 24.0%.

Effect of Hydrophilic/Hydrophobic Nanostructured TiO2 on Space Charge and Breakdown Properties of Polypropylene.

Polypropylene (PP) has received more and more attention in the field of insulating materials as a recyclable thermoplastic. To further enhance the applicability of polypropylene in the field of insulation, it needs to be modified to improve its electrical properties. In this paper, the impact mechanism of AEROXIDE® TiO2 P 90 (P90) and AEROXIDE® TiO2 NKT 90 (NKT90) as nanosized hydrophilic and hydrophobic fumed titania from Evonik on the electrical properties of PP was studied mainly through the crystallization behavior and space charge distribution of PP nanocomposites. Two kinds of nanostructured TiO2 were melt-blended with PP according to four types of contents. The results of alternating current (AC)/direct current (DC) breakdown field strength of the two materials were explained by studying the microstructure and space charge characteristics of the nanocomposites. Among them, hydrophilic nanostructured TiO2 are agglomerated when the content is low. The spherulite size of the nanocomposite is large, the space charge suppression ability is poor, the charge is easy to penetrate into the pattern, and the AC/DC breakdown field strength is significantly reduced. However, hydrophobic nanostructured TiO2 has better dispersion in PP, smaller spherulites, more regular arrangement, and less space charge accumulation. The charge penetration occurs only when the nanostructured material content is 2 wt%, and the AC/DC breakdown strength increases by 20.8% at the highest when the nanostructured material content is 1 wt%. It provides the possibility to prepare recyclable high-performance DC PP composite insulating materials.

Case report of a Japanese patient with chronic renal failure who developed SARS-CoV-2 in a hospital cluster during treatment for acute respiratory failure: An autopsy report.

This article reports a clinical and histopathological perspective which noted not only COVID-19 pneumonia but also exacerbation of chronic renal failure potentially caused by thrombus in the kidney, possibly COVID-19-related lesions. The accumulation of autopsy cases will elucidate the pathogenesis of COVID-19 and aid in the development of effective therapeutics.

Novel acid trehalase belonging to glycoside hydrolase family 37 from Pleurotus sp.: cloning, expression and characterization.

The N-terminal amino acid sequence of the Pleurotus sp. 90 kDa protein was in good agreement with the corresponding sequence of the glycoside hydrolase (GH) family 37 protein (trehalase) from P. ostreatus PC 15 v2.0. The length of the Pleurotus sp. trehalase gene was 2247 bp, encoding a protein of 749 amino acids with a predicted molecular mass of 81.2 kDa. The molecular mass of the recombinant enzyme was estimated to be about 117 kDa by SDS-PAGE. We found that the recombinant enzyme comprised an N-glycosylated sugar chain and that its optimum pH and temperature were 4.5 and 40 ºC, respectively. Moreover, this enzyme exhibited high activity against trehalose exclusively. We found that the enzyme is novel acid trehalase belonging to GH family 37.

Combination of anti-glycopeptidolipid-core IgA antibody and clinical features for diagnosing potential nontuberculous mycobacterium pulmonary disease in routine practice.

BACKGROUND: The anti-Mycobacterium avium complex (MAC) antibody test measures levels of IgA antibody against the glycopeptidolipid (GPL) core in the bacterial cell walls and is a useful clinical indicator of nontuberculous mycobacterium pulmonary disease (NTM-PD). However, it is not currently possible to diagnose the disease using anti-MAC antibodies alone. OBJECTIVES: The study aim was to assess the efficacy of the combination of anti-MAC antibodies and clinical findings for diagnosing potential NTM-PD. METHODS: This cross-sectional study included 938 patients tested using the anti-MAC antibody. NTM-PD was diagnosed by multiple positive cultures of the same species in sputum samples. Multivariate logistic regression models were used to identify the clinical factors related to NTM-PD. RESULTS: Overall, 19.6% (184/938) of participants were diagnosed with NTM-PD. In multivariate analysis, positive anti-MAC antibodies, low body mass index, absence of malignancy, and cavity-forming lung lesions were significantly associated with NTM-PD at diagnosis. The positive rates of the anti-MAC antibody test were 79.4% (135/170) for MAC and 55.6% (5/9) for Mycobacterium abscessus complex, respectively. CONCLUSIONS: Bronchoscopic examinations should be performed especially in certain types of individuals from whom sputum samples cannot be obtained. Anti-MAC antibodies are also positive in patients other than those harboring MAC, but the rate may be low because of the different components in GPLs.

Novel ribbon-type nuclear factor of activated T cells decoy oligodeoxynucleotides preclude airways hyperreactivity and Th2 cytokine expression in experimental asthma.

BACKGROUND: Nuclear factor of activated T cells (NFAT) is required for the differentiation of Th2 responses, so we examined its role in mouse experimental asthma and tested the hypothesis that an NFAT blockade with a decoy against NFAT can prevent asthma progression. OBJECTIVE: To determine the effects of the NFAT decoy oligodeoxynucleotides (ODNs) on the development of airway inflammation, we designed a novel ribbon-type ODN containing two binding sites for NFAT in a single decoy molecule without an open end, which is more stable than a conventional decoy, and largely preserved its structural integrity in the presence of nucleases. METHODS: Ribbon-type NFAT decoy ODNs were transfected into ovalbumin (OVA)-sensitized CD3+ T cells in vitro. OVA-immunized mice received these cells by intraperitoneal injection. Airway hyperreactivity (AHR) was measured and the transfected CD3+ T cells' responses to the airways were characterized. RESULTS: Development of AHR after OVA challenge was effectively abolished after adoptive transfer of ribbon-type NFAT decoy ODN transfected CD3+ T cells. Transfer of ribbon-type decoy significantly reduced the number of inflammatory cells and the concentrations of IL-4, IL-5 and IL-13, but not IFN-γ, in the bronchoalveolar lavage of the recipient mice. CONCLUSION: These results suggest the inhibitory effect of ribbon-type decoy ODNs against NFAT on the induction of bronchial asthma. Adoptively transferred CD3+ T cells, which are transfected with NFAT decoy, may be an effective strategy for the treatment of asthma.

[Roles of histamine in the pathogenesis of bronchial asthma and reevaluation of the clinical usefulness of antihistamines].

Histamine has been reported to play an important role in pathogenesis of bronchial asthma. However, H1-blockers are not recommended as the first drug for asthma therapy in the guidelines. Histamine may play various roles in allergic airway inflammation through the H1 receptor (H1R), H2R, and H4R in immune cells including T lymphocytes and dendritic cells. We therefore evaluated its role in allergic airway inflammation with the use of histamine-deficient mice. The results suggested that histamine plays a role in the prevention of goblet cell hyperplasia. Organic cation transporter-3 (OCT-3) is thought to be a transporter of histamine. Polymorphism of OCT-3 {R120R (T/C)} was associated with the severity of asthma. Recently, it has been proposed that both asthma and allergic rhinitis should be treated as a single airway disease. Comorbidity of asthma and allergic rhinitis is very high (70-80%) and they share similar allergic inflammation. H1-blockers are recommended as first-line drugs to treat allergic rhinitis in the guidelines. Therefore H1-blockers are strongly recommended for patients with both asthma and allergic rhinitis.

Analysis of pulmonary allergic vasculitis with eosinophil infiltration in asthma model of mice.

Here the authors report pulmonary allergic vasculitis with eosinophil infiltration in an asthma model of mice and investigated its pathogenesis. C57BL/6 and BALB/c mice were sensitized with ovalbumin (OVA). After the inhalation of OVA, the authors measured the cell number and cytokine concentration in the blood and bronchoalveolar lavage fluid (BALF). The authors also examined the histological changes of the pulmonary. The number of eosinophils increased in the blood and BALF in both strains; however, the number in C57BL/6 in BALF was significantly higher than that in BALB/c. Histological analysis demonstrated severe vasculitis of the pulmonary arteries with derangement of the muscle layer and smooth muscle cell hyperplasia in C57BL/6. Semiquantitative analysis of the severity of vasculitis in the pulmonary arteries revealed that the internal vascular space was highly reduced by smooth muscle hyperplasia in C57BL/6 compared to BALB/c mice. The concentrations of interleukin (IL)-4, IL-5, and interferon (IFN)-gamma in BALF of C57BL/6 were significantly high compared to those of BALB/c. C57BL/6 mice exhibited severe allergic vasculitis in the pulmonary arteries compared to BALB/c mice. The high concentrations of IL-4, IL-5, and IFN-gamma in the lung may play a critical role in the pathogenesis of allergic vasculitis in C57BL/6 mice.

Japanese mushroom consumption alters the lipid metabolomic profile of high-fat diet-fed mice.

Mushrooms are familiar ingredients in Japanese cuisine and large numbers are consumed in Japan. Recently, we reported that the consumption of Japanese mushrooms suppressed the accumulation of visceral fat. The purpose of this study was to examine the alteration of lipid metabolism by Japanese mushrooms consumption in high-fat diet (HFD) mice. Multivariate analysis of serum, liver, adipose tissue, cecal contents, large intestinal and fecal lipids showed differing compositions in the mice that had consumed HFD or HFD supplemented with 3% freeze-dried mushroom mixture (HFMD). There were higher concentrations of diacylglycerol in the adipose tissue, non-esterified fatty acids in the serum, and triacylglycerol in the feces of the HFMD group. These results suggest that mushroom consumption promotes the degradation of lipids in visceral fat and limits the absorption of food lipids. Moreover, the HFMD group demonstrated higher concentrations of phospholipids, some of which contained odd-chain fatty acids. Thus, we speculated that the alteration of lipid metabolism in mice such that mushroom consumption prevent obesity progression, as demonstrated by metabolomic analysis.

Genetically Independent Tetranucleotide to Hexanucleotide Core Motif SSR Markers for Identifying Lentinula edodes Cultivars.

For the purpose of protecting the rights of Lentinula edodes breeders, we developed a new simple sequence repeat (SSR) marker set consisting only of genetically independent tetranucleotide or longer core motifs. Using available genome sequences for five L. edodes strains, we designed primers for 13 SSR markers that amplified polymorphic sequences in 20 L. edodes cultivars. We evaluated the independence of every possible marker pair based on genotype data. Consequently, eight genetically independent markers were selected. The polymorphic information content values of the markers ranged from 0.269 to 0.764, with an average of 0.409. The markers could distinguish among 20 L. edodes cultivars and produced highly repeatable and reproducible results. The markers developed in this study will enable the precise identification of L. edodes cultivars, and may be useful for protecting breeders' rights.

[Advocating the diagnostic criteria for early stage of asthma].

BACKGROUND: In asthmatic patients, first asthmatic symptoms are not often typical. In those cases, it takes long time before asthma diagnosis, and the severities are progressed in some patients. For early intervention, we tried to make the diagnostic criteria for asthma, which are useful to diagnose as early stage of asthma. METHODS: Three hundred and eighty eight of asthmatic patients, who were recorded first their symptoms in asthma, were enrolled. Their first symptoms and examinations were analyzed. RESULTS: In first asthmatic symptoms, 79% of patients had cough, 68% patients had wheezing, 49% patients had dyspnoea, and 15% of patients did not have typical asthmatic symptoms in the early stage. The percentages of abnormal in first examinations were 99% in airway hypersensitivity, 92% of low %V25, 82% of eosinophila in sputum and 77% of low %V50. Low FEV1% and reversible airway obstruction were not seen in a lot of patients. CONCLUSION: We advocate that the diagnostic criteria for early stage of asthma are the following three elements. First criterion is spasmodic cough, wheezing and dyspnoea. Second criterion is airway hypersensitivity, or over 3% of eosinophils in sputum, or under 70% of %V50, or under 50% of %V25, or effect of bronchodilator. Effect of bronchodilator will be required, when the symptom is cough only. Third criterion is the exclusion of other lung and heart diseases.

4-Pyridoxolactonase from a symbiotic nitrogen-fixing bacterium Mesorhizobium loti: cloning, expression, and characterization.

4-Pyridoxolactonase is involved in the degradation pathway for pyridoxine, a free form of vitamin B6. The gene (mlr6805) encoding the putative 4-pyridoxolactonase of nitrogen fixing symbiotic microorganism Mesorhizobium loti MAFF303099 has been identified based on the genome database. The gene was cloned and overexpressed in a cotransformant Escherichia coli cell. The recombinant enzyme was dimeric protein and contained one mole of Zn2+ per mole of subunit. The enzyme showed about 30% identity with various N-acylhomoserine lactone lactonases and metallo-beta-lactamases. The phylogram made with ClustalW shows that 4-pyridoxolactonase makes a cluster with Agrobacterium tumefaciens acyl-homoserine lactone lactonase. The alignment of amino acid sequences suggests that 4-pyridoxolactonase has three histidine residues probably involved in binding of Zn2+.

[Effects of proton pump inhibitor on airway hyperresponsiveness in asthmatics with gastroesophageal reflux].

BACKGROUND: Previous data suggest the high incidence of gastroesophageal reflux (GER) in asthmatics, although the relationship between GER and the respiratory condition in asthmatics remain unclear. We investigated the incidence of GER in asthmatics and the association between the effects of proton-pump inhibitor (PPI) on respiratory functions and esophageal pH in asthmatics with GER. METHODS: Two hundreds ninety outpatients who attended our unit with asthma received GER symptoms questionnaire used at Mayo Clinic. Twenty three of them who answered to have any GER symptom were treated with PPI (lansoprazole 30 mg/day) for eight weeks, and investigated changes in the GER symptoms and peak expiratory flow rates (PEFR) before and after treatment. Furthermore, in six of twenty three, airway hyperresponsiveness to methacholine and esophageal pH monitor for 24 hours were measured in order to evaluate the association between esophageal pH and the effect of PPI on GER during the test. Furthermore, the serum level of theophylline was analyzed for assessment of the PPI effect on theophylline metabolism. RESULTS: 150 of 290 asthmatics had answered to have any GER symptom including cough. Most of GER symptoms had improved except for cough after treatment with PPI. The airway hyperresponsiveness significantly improved after treatment with PPI (n=6, p<0.03), although PEF and FEV1 were not significantly changed. CONCLUSION: These results suggest that PPI may be an effective drug for asthmatics with GER through suppression of airway hyperresponsiveness.

[Predicted vales of respiratory function tests in young Japanese aged from 10 to 20 years].

To find predicted values of respiratory function tests in young persons in Japan, we measured slow vital capacity and forced vital capacity in 1,141 subjects aged from 10 to 20 years. The values obtained from 636 persons (363 males and 273 females) who were not smokers or had no suspected rhinitis or asthma were analyzed. Although FEV1% by the Gaensler and Tiffeneau methods were almost constant regardless of age, all other values of respiratory function tests increased with age and then reached a plateau level in late teens. Excluding the Gaensler and Tiffeneau FEV1%, in a single regression analysis using gender, age, and height, both the contribution ratio and regression coefficient were the highest using height, followed by age. In addition, the result was similar with multiple regression analysis. Therefore, for a young person aged from 10 to 20 years, body height is the most important predictor variable of respiratory function tests, compared to gender and age. For each respiratory function test, we showed the prediction relation according to gender obtained from multiple linear regression analysis using 2 variables of height and age.

Fractional exhaled nitric oxide levels as a predictor of long-term prognoses in patients with mild asthma.

BACKGROUND: There is a growing belief that patients with bronchial asthma (BA) should be provided an individualized and optimized treatment plan. We aimed to clarify the predictors of long-term prognoses in patients with mild BA. METHODS: We conducted a retrospective study of consecutive patients who were newly diagnosed with mild BA at Iwate Medical University from 2011 to 2013, focusing on achievement of full asthma control based on the Asthma Control Test as an indicator of prognosis. Predictors were identified on the basis of a chart review. RESULTS: Among 71 patients with mild BA, 37 patients completed regular clinic visits for 1 year. Nineteen (51.4%) of these patients achieved full asthma control. Current smoking and the fractional exhaled nitric oxide (FeNO) level at the first patient visit were identified by multivariate logistic regression as possible predictors of the discontinuation of clinic visits and achievement of full asthma control, respectively. Low FeNO levels at the first clinic visit yielded a receiver operating characteristic-area under the curve of 0.860 (95% confidence interval [CI]=0.774-0.975) for the achievement of full asthma control. Using an FeNO cut-off level of 34 parts per billion yielded a sensitivity of 76.5% (95% CI=59.5-88.2%) and specificity of 73.7% (95% CI=58.5-84.2%). CONCLUSION: Our preliminary results suggested that patients with newly diagnosed mild BA who display higher FeNO levels at their first clinic visits should be appropriately educated during early visits to receive optimal treatment and complete regular clinic visits.

Molecular cloning and characterization of oryzacystatin-III, a novel member of phytocystatin in rice (Oryza sativa L. japonica).

On the basis of cDNA sequences, we found that the calli of rice encodes an amino acid sequence that shares 56% and 89% identity, respectively, with oryzacystatin-I and oryzacystatin-II. This sequence differs from that of oryzacystatin-II in the N-terminal region (Gln(7)-Ala(19) in the oryzacystatin-III numbering), and this region contained a glycine residue (Gly(14)), which is evolutionarily conserved in the cystatin superfamily. We named this novel protein oryzacystatin-III. Nucleotide sequencing of the 5'-flanking region of the oryzacystatin-III gene showed that it is highly homologous to the oryzacystatin-II gene but distinct from the oryzacystatin-II locus. Oryzacystatin-III inhibited papain, ficin, and human cathepsin B. The inhibition constants for papain and ficin differ from those of oryzacystatin-I and -II, and cathepsin B activity is affected only by oryzacystatin-III, showing differences in the interaction of these inhibitors with enzymes. These data suggest that the above three inhibitors may play unique physiological roles in the regulations of rice cysteine proteinases.

Lymphangiogenic factors are associated with the severity of hypersensitivity pneumonitis.

BACKGROUND: Antigen presenting cells play a pivotal role in the adaptive immune response in hypersensitivity pneumonitis (HP). It was hypothesised that lymphangiogenesis is involved in the pathophysiology of HP via cell transport. OBJECTIVE: To determine the clinical significance of lymphangiogenic factors in HP. METHODS: Levels of vascular endothelial growth factors (VEGF)-A, VEGF-C, VEGF-D and CCL21 in the serum and bronchoalveolar lavage fluid (BALF) were measured in 29 healthy volunteers, 14 patients with idiopathic pulmonary fibrosis (IPF) and 26 patients with HP by ELISA. Additionally, immunohistochemical analyses were performed using lung specimens of patients with HP (n=8) and IPF (n=10). RESULTS: BALF VEGF-D levels were significantly elevated in patients with HP compared to the other groups. BALF VEGF-D levels in patients with HP correlated significantly with the BALF total cell and lymphocyte counts (r=0.485, p=0.014 and r=0.717, p<0.0001, respectively). BALF VEGF-C and CCL21 levels were increased in patients with HP compared to healthy volunteers, but not patients with IPF. BALF CCL21 levels were negatively correlated with the forced expiratory volume in 1 s percentage and diffuse capacity of the lung for carbon monoxide (r=-0.662, p=0.007 and r=-0.671, p=0.024, respectively). According to the immunohistochemical analyses, CCL21 was expressed in the lymphatic endothelium in both conditions and CCR7(+) cells were aggregated around lymphatics in patients with HP, but not in patients with IPF. CONCLUSIONS: Lymphangiogenic factors might be associated with the inflammatory and functional severity of HP. The increased BALF VEGF-D levels were associated with lymphatic alveolitis intensity, and CCL21 with lung function impairment.