while the recent strategies of lung - protective ventilation and proper fluid restriction therapy have reduced mortality in patients with acute lung injury ( ali ) and acute respiratory distress syndrome ( ards ) , the mortality rate remains high .
although many pharmacological therapies have been attempted to treat ali / ards , no specific therapy has demonstrated a clear effect so far .
accordingly , mesenchymal stem cells ( mscs ) have been introduced as a possible therapy .
mscs are multipotent adult stem cells that have the ability to differentiate into many different cell lineages and the capacity for self - renewal ( 1 ) .
in early research on the use of mscs to treat ali / ards , the main mechanism of action of these cells seemed likely to involve the replacement of injured lung epithelium . however , subsequent studies have suggested that the most important therapeutic effect probably comes from the paracrine properties of mscs ( 2 , 3 ) .
thus far , the therapeutic potentials of mscs have primarily been supported by preclinical evidence and the need for clinical trials has been suggested ( 4 ) . as there is a lack of clinical data , we here introduce a patient who was treated with mscs in the course of ards and subsequent pulmonary fibrosis .
a 59-yr - old man with a history of pulmonary tuberculosis ( tb ) and no significant family history was diagnosed with idiopathic thrombocytopenia in june 2008 .
, he developed a cough , sputum , and rhinorrhea and five days later displayed fever and dyspnea .
his chest radiography and computed tomography ( ct ) scan showed multifocal patchy ground - glass opacities ( ggos ) in both lungs with underlying emphysema with large bullae in the left lower lobe and focal irregular nodular lesions in the right upper lobe that were presumed to be tb sequelae .
after five days , he was transferred to our hospital , a tertiary referral center , and admitted to the medical intensive care unit . at admission , he had tachypnea with a fever of 39. he had progressive bilateral diffuse infiltrations on his chest radiography .
his initial sao2 level was 75% and his pao2/fio2 ( p / f ) ratio was 166 mmhg .
we started a course of methylprednisolone at a dose of 40 mg twice a day to treat a possible pneumocystis jiroveci pneumonia in conjunction with a continuing regimen of empirical antibiotics and an antiviral agent .
however , no specific pathogen was identified in any specimen from this patient , including bronchoalveolar lavage , blood or sputum .
then , his chest radiography was stationary and his p / f ratio began to gradually improve . on hospital day ( hd ) 7 , he underwent tracheostomy to enable early weaning from mv .
however , he then developed hospital - acquired pneumonia and hydropneumothorax due to a ruptured bullae with bronchopulmonary fistula ( bpf ) .
he was conscious during this time but he could not communicate with the medical team or even his family members .
on hd 87 , he had a follow - up high - resolution ct , which showed aggravation of diffuse ggos and interlobular septal thickening in both lungs .
this indicated the progression of pulmonary fibrosis as a post - ards sequelae . after discussing the possibility of administering mscs with his family , we commenced with a trial of this therapy .
the umbilical cord blood ( ucb)-derived mscs ( ucb - mscs ) were prepared as follows .
ucb - mscs were produced at the good manufacturing practice facility of medipost co. , ltd .
quality control and quality assurance for the production of these cells were performed according to the standards of the korea food and drug administration .
flow cytometry analysis of expressed surface antigens showed that these cells were uniformly positive for cd29 , cd44 , cd73 , cd105 , and cd166 and negative for the hematopoietic lineage markers cd34 , cd45 , cd14 , and hla - dr .
the final ucb - mscs preparations used in the infusion were harvested from cell culture passage 6 and suspended at a final density of 7.510/1.5 ml in normal saline . on hd 114 , the patient underwent the intratracheal administration of ucb - mscs at a target dose of 110/kg . before the procedure , the ventilator was set to the pressure - controlled ventilation ( pcv ) mode of 26 cmh2o of inspiratory pressure ( ip ) and 0.45 of fio2 .
there were no peri - procedural complications . the next morning ( 16 hr later )
, he was able to communicate effectively with our medical team , which had not been possible in the previous few months .
after 24 hr , we changed the pcv to a pressure support mode with 18 cmh2o of support pressure with 0.4 of fio2 .
after 48 hr , pcv was applied again with 22 cmh2o with 0.35 of fio2 .
the dynamic compliance of his lung improved from a pre - procedure value of 22.7 to 26.5 , 27.3 , and 27.9 ml / cmh2o after 24 , 48 , and 72 hr , respectively .
his p / f ratio subsequently increased from pre - procedural 191 to 328 mmhg on day 1 after the procedure and to 334 mmhg on day 3 ( fig .
1 ) . a follow - up chest radiography showed a slight decrease in bilateral lung infiltrates ( fig .
2 ) . on day 3 , however , he suddenly experienced six generalized tonic - clonic seizures during the course of the day with a fever near to 39. he had no focal lateralizing signs . a brain ct was performed and showed no hemorrhage .
we discussed the case with neurological specialists and determined that the current use of carbapenem was the most probable cause of his seizure .
the weaning trial was restarted for our patient and the ip was reduced to 12 cmh2o with 0.3 of fio2 during the following week .
however , he could not be weaned because his repeated infection by multidrug - resistant pathogens was not controlled .
eventually , he suffered septic shock due to empyema and died on hd 231 or day 118 after msc administration .
our current case involved a patient who developed ards due to pneumonia . he subsequently had post - ards pulmonary fibrosis . weaning from mv was difficult as he did not improve for a long - period ( four months ) .
although he failed to survive , his immediate improvement after cell infusion is worthy of mention . his mental status ,
his lung compliance , p / f ratio and his chest radiography all showed improvement over the course of at least three days .
we speculate that these clinical , physiological and radiological improvements might be related to the paracrine properties of mscs , with immunomodulation , alveolar fluid clearance and regulation of lung protein permeability known as potential mechanisms ( 2 ) .
the main reasons for our failure to help this patient survive by mscs therapy are likely to be the following .
first , his pulmonary fibrosis was so advanced that it could not respond to the stem cell therapy .
its effectiveness may depend mainly on paracrine activity rather than regeneration by stem cell engraftment .
thus , a long - term effect would not be expected due to his advanced stage of fibrosis .
second , his bpf - related repeat infections may have caused the lack of improvement in his lung compliance .
since the pathogens that were responsible for the infection were multidrug - resistant to current antibiotics , a proper antimicrobial treatment could not be performed in advance of the stem cell therapy . a third possible reason concerns the dose and the number of stem cells administered .
we intratracheally infused 110/kg stem cells on one occasion but no study regarding the proper number of cells for intrapulmonary administration in humans has thus far been reported .
accordingly , our dose was based on that used intravenously in a trial in acute graft - versus - host - disease after allogeneic hematologic stem cell transplantation ( 5 ) .
we decided to infuse using a local route as we expected more intrapulmonary action and less systemic adverse effects than for an intravenous injection .
however , our dose or the one - time - only administration may have been insufficient to produce a significant effect .
this report has a number of notable limitations that hinder the interpretation of the definite effect of mscs in post - ards pulmonary fibrosis .
first , we did not check the level of cytokines or other soluble factors that have been shown to be associated with the functions of mscs in preclinical studies .
in addition , our interpretation in this case study relied on clinical parameters and radiological images only .
thus , it is difficult to precisely link the patient 's short - term clinical improvement to the definite action of the mscs . finally ,
even though the clinical studies of msc therapy for acute lung injury are currently underway , there is no definite evidence so far .
thus , our decision on the msc therapy may have some ethical problems although we had no other way as a salvage therapy for his fibrotic stage of ards .
our current findings suggest the possibility of using msc therapy in an ards patient and it is the first clinical case of ucb - mscs therapy ever reported . for a clear verification of msc therapy in ali ,
 umbilical cord blood ( ucb)-derived mesenchymal stem cells ( mscs ) have been introduced as a possible therapy in acute lung injury and acute respiratory distress syndrome ( ards ) . 
 this case history is reported of a 59-yr - old man who was treated with mscs in the course of ards and subsequent pulmonary fibrosis . 
 he received a long period of mechanical ventilation and weaning proved difficult . on hospital day 114 , he underwent the intratracheal administration of ucb - derived mscs at a dose of 1  106/kg . 
 after cell infusion , an immediate improvement was shown in his mental status , his lung compliance ( from 22.7 ml / cmh2o to 27.9 ml / cmh2o ) , pao2/fio2 ratio ( from 191 mmhg to 334 mmhg ) and his chest radiography over the course of three days . 
 even though he finally died of repeated pulmonary infection , our current findings suggest the possibility of using mscs therapy in an ards patient . 
 it is the first clinical case of ucb - derived mscs therapy ever reported . 