CC16 augmentation reduces exaggerated COPD-like disease in Cc16-deficient mice.

Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke-exposed (CS-exposed) Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-κB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. RhCC16 treatment reduced NF-κB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-κB activation and represents a potentially novel therapeutic approach for COPD.

Emerging role of an immunomodulatory protein secretoglobin 3A2 in human diseases.

Secretoglobin (SCGB) 3A2 was first identified in 2001 as a protein exhibiting similarities in amino acid sequence and gene structure to SCGB1A1, a multi-functional cytokine-like molecule highly expressed in airway epithelial Club cells that was the first identified and extensively studied member of the SCGB gene superfamily. SCGB3A2 is a small secretory protein of ~10 kDa that forms a dimer and a tetramer. SCGB3A2 is predominantly expressed in airway epithelial Club cells, and has anti-inflammatory, growth factor, anti-fibrotic, and anti-cancer activities that influence various lung diseases. This review summarizes the current understanding of SCGB3A2 biological functions and its role in human diseases with emphasis on its mechanisms of actions and signaling pathway.

Secretoglobin 3A2 eliminates human cancer cells through pyroptosis.

Non-canonical inflammasome activation that recognizes intracellular lipopolysaccharide (LPS) causes pyroptosis, the inflammatory death of innate immune cells. The role of pyroptosis in innate immune cells is to rapidly eliminate pathogen-infected cells and limit the replication niche in the host body. Whether this rapid cell elimination process of pyroptosis plays a role in elimination of cancer cells is largely unknown. Our earlier study demonstrated that a multi-functional secreted protein, secretoglobin (SCGB) 3A2, chaperones LPS to cytosol, and activates caspase-11 and the non-canonical inflammasome pathway, leading to pyroptosis. Here we show that SCGB3A2 exhibits marked anti-cancer activity against 5 out of 11 of human non-small cell lung cancer cell lines in mouse xenographs, while no effect was observed in 6 of 6 small cell lung cancer cell lines examined. All SCGB3A2-LPS-sensitive cells express syndecan 1 (SDC1), a SCGB3A2 cell surface receptor, and caspase-4 (CASP4), a critical component of the non-canonical inflammasome pathway. Two epithelial-derived colon cancer cell lines expressing SDC1 and CASP4 were also susceptible to SCGB3A2-LPS treatment. TCGA analysis revealed that lung adenocarcinoma patients with higher SCGB3A2 mRNA levels exhibited better survival. These data suggest that SCGB3A2 uses the machinery of pyroptosis for the elimination of human cancer cells via the non-canonical inflammasome pathway, and that SCGB3A2 may serve as a novel therapeutic to treat cancer, perhaps in combination with immuno and/or targeted therapies.

CC16 Binding to α4ß1 Integrin Protects against Mycoplasma pneumoniae Infection.

Rationale CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases (asthma and chronic obstructive pulmonary disease). Objectives Although exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating antiinflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Methods Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, leucine-valine-aspartic acid (LVD), a known integrin-binding motif. Recombinant CC16 was generated with and without the putative integrin-binding site. A Mycoplasma pneumoniae mouse model and a fluorescent cellular adhesion assay were used to determine the impact of the LVD site regarding CC16 function during live infection and on cellular adhesion during inflammatory conditions. Measurements and Main Results CC16 bound to integrin α4ß1), also known as the adhesion molecule VLA-4 (very late antigen 4), dependent on the presence of the LVD integrin-binding motif. During infection, recombinant CC16 rescued lung function parameters both when administered to the lung and intravenously but only when the LVD integrin-binding site was intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. Conclusions We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.

Club Cell Protein, CC10, Attenuates Acute Respiratory Distress Syndrome Induced by Smoke Inhalation.

OBJECTIVES: To evaluate the dose effects of Recombinant human Club cell 10-kDa protein (rhCC10) on lung function in a well-characterized ovine model of acute respiratory distress syndrome (ARDS) induced by smoke inhalation injury (SII); specifically, the potential of rhCC10 protein to control the inflammatory response and protect pulmonary tissue and function following SII. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal intensive care unit. SUBJECTS: Thirty-six adult female sheep were surgically prepared and allocated into five groups (Sham (no SII), n = 6; 1 mg/kg/d CC10, n = 8; 3 mg/kg/d CC10, n = 7; 10 mg/kg/d CC10, n = 8; Control SII, n = 7). INTERVENTIONS: All groups except the sham group were subjected to SII with cooled cotton smoke. Then, the animals were placed on a ventilator, treated with 1, 3, and 10 mg/kg/d of intravenous rhCC10 or vehicle, divided evenly into two administrations per day every 12 h, fluid resuscitated, and monitored for 48 h in a conscious state. MEASUREMENTS AND MAIN RESULTS: The group treated with 10 mg/kg/d rhCC10 attenuated changes in the following variables: PaO2/FiO2 ratio, oxygenation index, and peak inspiratory pressure; neutrophil content in the airway and myeloperoxidase levels; obstruction of the large and small airways; systemic leakage of fluid and proteins, and pulmonary edema. CONCLUSIONS: In this study, high-dose rhCC10 significantly attenuated ARDS progression and lung dysfunction and significantly reduced systemic extravasation of fluid and proteins, normalizing fluid balance. Based on these results, rhCC10 may be considered a novel therapeutic option for the treatment of SII-induced ARDS.

The role of recombinant human CC10 in the prevention of chronic pulmonary insufficiency of prematurity.

BACKGROUND: Preterm neonates can develop chronic pulmonary insufficiency of prematurity (CPIP) later in infancy. Recombinant human CC10 protein (rhCC10) is an anti-inflammatory agent that could potentially prevent CPIP. METHODS: The safety and efficacy of a single intratracheal dose of rhCC10 in reducing CPIP at 12 months corrected gestational age (CGA) was evaluated in a Phase II double-blind, randomized, placebo-controlled, multisite clinical trial. Eighty-eight neonates were randomized: 22 to placebo and 22 to 1.5 mg/kg rhCC10 in the first cohort and 21 to placebo and 23 to 5 mg/kg rhCC10 in the second cohort. Neonates were followed to 12 months CGA. RESULTS: With CPIP defined as signs/symptoms, medical visits, hospital readmissions, and use of medications for respiratory complications at 12 months CGA, no significant differences were observed between rhCC10 or placebo groups. Only 5% of neonates had no evidence of CPIP at 12 months CGA. CONCLUSIONS: A single dose of rhCC10 was not effective in reducing CPIP at 12 CGA. Since most neonates had evidence of CPIP using these exploratory endpoints, it is essential to develop more robust outcome measures for clinical trials of respiratory medications in high-risk premature neonates.

A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death.

Intracellular lipopolysaccharide (LPS) triggers the non-canonical inflammasome pathway, resulting in pyroptosis of innate immune cells. In addition to its well-known proinflammatory role, LPS can directly cause regression of some tumors, although the underlying mechanism has remained unknown. Here we show that secretoglobin(SCGB)3A2, a small protein predominantly secreted in airways, chaperones LPS to the cytosol through the cell surface receptor syndecan-1; this leads to pyroptotic cell death driven by caspase-11. SCGB3A2 and LPS co-treatment significantly induced pyroptosis of macrophage RAW264.7 cells and decreased cancer cell proliferation in vitro, while SCGB3A2 treatment resulted in reduced progression of xenograft tumors in mice. These data suggest a conserved function for SCGB3A2 in the innate immune system and cancer cells. These findings demonstrate a critical role for SCGB3A2 as an LPS delivery vehicle; they reveal one mechanism whereby LPS enters innate immune cells leading to pyroptosis, and they clarify the direct effect of LPS on cancer cells.

FLT3 Inhibitors in the Management of Acute Myeloid Leukemia.

In recent years there has been a great improvement in molecular characterization of acute myeloid leukemia (AML) allowing the stratification of patients in different rate of risk. Patients with FLT3 mutated AML have poor prognosis because of resistance to induction chemotherapy or early relapse. Several first and second generation molecules, able to inhibit FLT3 signaling have been developed and many single agent or combination studies are ongoing. Of these, quizartinib seems to have the best clinical activity. Unfortunately, resistance to FLT3 inhibitors has been observed and many scientists are currently investigating new strategy to restore sensitivity to FLT3 inhibitors.

Evaluation of Club Cell 10-kDa Protein (CC10) Levels in Full-Term Infants.

BACKGROUND: The club cell 10-kDa protein (CC10) is a homeostatic protein that is produced in the lung, diffuses into the blood, and is then excreted into the urine and stool. CC10 is known to have anti-inflammatory properties and to have lower endogenous production in preterm infants. OBJECTIVES: As recombinant human CC10 (rhCC10) is being studied in preterm infants to reduce lung injury, understanding CC10 levels in term infants with normal lungs is needed to establish appropriate target dosing ranges. METHODS: Serum, urine, and stool samples were collected from 24 healthy full-term infants, and CC10 levels were measured. Levels in term infants were then compared to those in preterm infants who were examined in our previous studies. RESULTS: The mean gestational age and birth weight of the term infants were 38.8 ±1.1 weeks and 3,257 ± 513 g, respectively. The mean gestational age of the preterm infants was 26.8 ± 1.4 weeks. The median serum [CC10] levels with minimum and maximum values in term infants (214.2 ng/mL [34.1, 428.1]) were >7-fold higher than in preterm infants (27.5 ng/mL [8.0, 760.0]; p < 0.05). A significant correlation was found between [CC10] in urine and stool as well as between gestational age and stool [CC10] (p < 0.05). CONCLUSIONS: CC10 is detectable in serum, urine, and stool in healthy term infants, with levels significantly higher than in preterm infants. This provides important data for ongoing therapeutic intervention trials with rhCC10 in high-risk preterm infants.

A solitary uterine relapse in T-cell Acute Lymphoblastic Leukaemia: CT features and pathologic correlation.

T-cell Acute Lymphoblastic Leukemia (T-cell ALL) is a rare haematological neoplasia, that affects children and less commonly adults. Female genital tract and particularly uterus involvement in acute ALL is rare. This report presents the CT features of a 64-year-old woman with uterine relapse of T-cell ALL, occurring 11 months after the diagnosis, as a second, unique relapse of disease. The patient was asymptomatic when a CT examination showed a homogenous thickness of the uterine wall in comparison with the previous CT examination. Histology from biopsy specimens, obtained through hysteroscopy, confirmed T-cell ALL localisation (TdT+, CD10+, CD3c+ and CD2+). The uterus could be a site of relapse in patients suffering from ALL. Even though an MRI examination could better demonstrate the disease in cases of suspected female genital tract involvement by ALL, the comparison of differences between a present and a previous CT examination is sufficient to suspect the diagnosis.

Protective role for club cell secretory protein-16 (CC16) in the development of COPD.

Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

Saliva transit in patients with gastroesophageal reflux disease.

Saliva is an important factor in the neutralization of the acidity of the refluxed material that comes from the stomach to the esophagus. The impairment of saliva transit from oral cavity to distal esophagus may be one of the causes of esophagitis and symptoms in gastroesophageal reflux disease (GERD). With the scintigraphic method, the transit of 2 mL of artificial saliva was measured in 30 patients with GERD and 26 controls. The patients with GERD had symptoms of heartburn and acid regurgitation, a 24-hour pH monitoring with more than 4.2% of the time with pH below four, 26 with erosive esophagitis, and four with non-erosive reflux disease. Fourteen had mild dysphagia for solid foods. Twenty-one patients had normal esophageal manometry, and nine had ineffective esophageal motility. They were 15 men and 15 women, aged 21-61 years, mean 39 years. The control group had 14 men and 12 women, aged 19-61 years, mean 35 years. The subjects swallowed in the sitting and supine position 2 mL of artificial saliva labeled with 18 MBq of (99m) Technetium phytate. The time of saliva transit was measured from oral cavity to esophageal-gastric transition, from proximal esophagus to esophageal-gastric transition, and the transit through proximal, middle, and distal esophageal body. There was no difference between patients and controls in the time for saliva to go from oral cavity to esophageal-gastric transition, and from proximal esophagus to esophageal-gastric transition, in the sitting and supine positions. In distal esophagus in the sitting position, the saliva transit duration was shorter in patients with GERD (3.0 ± 0.8 seconds) than in controls (7.6 ± 1.7 seconds, P = 0.03). In conclusion, the saliva transit from oral cavity to the esophageal-gastric transition in patients with GERD has the same duration than in controls. Saliva transit through the distal esophageal body is faster in patients with GERD than controls.

Preclinical evaluation of human secretoglobin 3A2 in mouse models of lung development and fibrosis.

Secretoglobin (SCGB) 3A2 is a member of the SCGB gene superfamily of small secreted proteins, predominantly expressed in lung airways. We hypothesize that human SCGB3A2 may exhibit anti-inflammatory, growth factor, and antifibrotic activities and be of clinical utility. Recombinant human SCGB3A2 was expressed, purified, and biochemically characterized as a first step to its development as a therapeutic agent in clinical settings. Human SCGB3A2, as well as mouse SCGB3A2, readily formed a dimer in solution and exhibited novel phospholipase A2 inhibitory activity. This is the first demonstration of any quantitative biochemical measurement for the evaluation of SCGB3A2 protein. In the mouse as an experimental animal, human SCGB3A2 exhibited growth factor activity by promoting embryonic lung development in both ex vivo and in vivo systems and antifibrotic activity in the bleomycin-induced lung fibrosis model. The results suggested that human SCGB3A2 can function as a growth factor and an antifibrotic agent in humans. When SCGB3A2 was administered to pregnant female mice through the tail vein, the protein was detected in the dam's serum and lung, as well as the placenta, amniotic fluids, and embryonic lungs at 10 min postadministration, suggesting that SCGB3A2 readily crosses the placenta. The results warrant further development of recombinant SCGB3A2 as a therapeutic agent in treating patients suffering from lung diseases or preterm infants with respiratory distress.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function.

BACKGROUND: The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). METHODS: Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. KEY RESULTS: In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. CONCLUSIONS & INFERENCES: There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.

Recombinant human Clara cell secretory protein treatment increases lung mRNA expression of surfactant proteins and vascular endothelial growth factor in a premature lamb model of respiratory distress syndrome.

Infant respiratory distress syndrome (IRDS) can lead to impaired alveolarization and dysmorphic vascularization of bronchopulmonary dysplasia. Clara cell secretory protein (CC10) has anti-inflammatory properties but is deficient in the premature infant. Because surfactant and vascular endothelial growth factor (VEGF) profiles are impaired by inflammation and CC10 inhibits lung inflammation, we hypothesized that CC10 may up-regulate surfactant protein (SP) and VEGF expression. Preterm lambs ( N = 24; 126 +/- 3 days [standard error] gestation) with IRDS were randomized to receive 100 mg/kg surfactant, 100 mg/kg surfactant followed by intratracheal 0.5, 1.5, or 5 mg/kg rhCC10 and studied for 4 hours. Gas exchange and lung mechanics were monitored; surfactant protein and VEGF mRNA profiles in lung were assessed. There was a significant rhCC10 dose-dependent increase in respiratory compliance and ventilation efficiency index; both parameters were significantly greater in animals treated with 5 mg/kg rhCC10 than those treated with surfactant alone. Similarly, there was a significant rhCC10 dose and protein-dependent increase in surfactant protein (SP-B > SP-C > SP-A) and dose- and isoform-dependent increase in VEGF (VEGF189 > VEGF165 > VEGF121). These data demonstrate that early intervention with rhCC10 up-regulates surfactant protein and VEGF expression, supporting the role of CC10 to protect against hyperoxia and mechanical ventilation in the immature lung.

Postprandial gastric antral contractions in patients with gastro-oesophageal reflux disease: a scintigraphic study.

Disturbed gastric contractility has been found in manometric studies in patients with gastro-oesophageal reflux disease (GORD), but the pathophysiological role of this abnormality is unclear. We aimed at assessing postprandial gastric antral contractions and its relationships with gastric emptying and gastro-oesophageal reflux in GORD patients. Fasted GORD patients (n = 13) and healthy volunteers (n = 13) ingested a liquid meal labelled with 72 MBq of 99mTechnetium-phytate. Gastric images were acquired every 10 min for 2 h, for measuring gastric emptying half time. Dynamic antral scintigraphy (one frame per second), performed for 4 min at 30-min intervals, allowed estimation of both mean dominant frequency and amplitude of antral contractions. In GORD patients (n = 10), acidic reflux episodes occurring 2 h after the ingestion of the same test meal were determined by ambulatory 24-h oesophageal pH monitoring. Gastric emptying was similar in GORD patients and controls (median; range: 82 min; 58-126 vs 80 min; 44-122 min; P = 0.38). Frequency of antral contractions was also similar in both groups (3.1 cpm; 2.8-3.6 vs 3.2 cpm; 2.4-3.8 cpm; P = 0.15). In GORD patients, amplitude of antral contractions was significantly higher than in controls (32.7%; 17-44%vs 23.3%; 16-43%; P = 0.01), and correlated positively with gastric emptying time (R(s) = 0.58; P = 0.03) and inversely with the number of reflux episodes (R(s) = -0.68; P = 0.02). Increased amplitude of postprandial gastric antral contractions in GORD may comprise a compensatory mechanism against delayed gastric emptying and a defensive factor against acidic gastro-oesophageal reflux.

CC10 reduces inflammation in meconium aspiration syndrome in newborn piglets.

Complications from meconium aspiration syndrome (MAS) remain significant despite a variety of therapeutic interventions. Clara cell protein (CC10) is a novel anti-inflammatory agent that can also inhibit phospholipase A2 (PLA2) (an important component of meconium). The present study examined whether administration of recombinant human CC10 (rhCC10) would reduce inflammation and improve lung function in a piglet model of MAS. Following meconium instillation, piglets exhibited significant physiologic dysfunction that improved significantly after surfactant administration. Analysis of tracheal aspirates revealed significant increases in both tumor necrosis factor (TNF) alpha and interleukin (IL)-8 after meconium instillation. rhCC10-treated animals had significantly lower TNF-alpha levels at 24 h (561 +/- 321 versus 1357 +/- 675 pg/mL, p < 0.05) compared with saline controls. There were no differences between rhCC10-treated and untreated groups with respect to other measured physiologic variables or inflammatory markers, including secretory PLA2 activity. Histologic analyses revealed marked inflammatory infiltrates and thickened alveolar walls, but no significant differences among rhCC10 and control animals. Newborn piglets with MAS have significant physiologic dysfunction, marked inflammatory changes and histologic abnormalities, which was partially counteracted by a single dose of exogenous surfactant and rhCC10.

Effects of recombinant Clara cell secretory protein (rhCC10) on inflammatory-related matrix metalloproteinase activity in a preterm lamb model of neonatal respiratory distress.

OBJECTIVE: To test the hypothesis that recombinant Clara cell secretory protein (rhCC10) instillation would foster improved lung function, acute structural preservation, and attenuation of matrix metalloproteinase (MMP) activity in a surfactant-deficient, mechanically ventilated lung. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in the northeastern United States. SUBJECTS: Sedated, ventilated premature lambs. INTERVENTIONS: Preterm lambs (n = 18; 126 +/- 3 days gestation) were instrumented, ventilated, and treated with 100 mg/kg exogenous surfactant. Lambs were randomized to receive 0, 0.5, or 5.0 mg/kg rhCC10 (n = 6 per group) and were ventilated for 4 hrs. MEASUREMENTS AND MAIN RESULTS: Posttreatment, lung function and cardiopulmonary stability were monitored for the ventilation period and then animals were killed for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, -7, and -9 as well as their tissue inhibitors (TIMP)-1 and -2. Ventilation efficiency and pulmonary compliance were improved in the 5.0-mg/kg rhCC10 group by 4 hrs. Lung expansion was variable in the apical regions only. MMP-2 quantity was greater in the apical than the base lung regions of rhCC10-treated groups, and rhCC10 decreased MMP-7 in the base of the lung. CONCLUSIONS: These data suggest that improved lung function in the surfactant-treated preterm lamb following intratracheal rhCC10 may be related to the reduction of proteolytic activity of MMP-7.