Disease and injury in the lung can be attributable to genetic abnormalities, such as in the case of patients suffering from cystic fibrosis, or acute or chronic injury and disease, such as disorders resulting from inhalation exposure. As the etiology of many lung diseases, such as idiopathic pulmonary fibrosis, are often poorly understood, determining and treating the root cause of lung dysfunction often becomes secondary to managing and inhibiting disease progression.

Whatever the cause, the first hurdle when treating the lung is understanding the geographical complexity of the affected region. Consequently, this means that multiple cell lineages and niches are likely responsible for repopulating and driving homeostasis in the injured or diseased lung. Compounded with the fact that many of the stem and progenitor cellular niches within the human lung are still not fully characterized, designing effective stem cell-based treatments and therapies to target or repopulate specific cell lineages is quite challenging.

In the case of acute pulmonary injury, such as in acute respiratory distress syndrome, immediate medical and surgical intervention is often necessary. Patients are often monitored closely throughout recovery and respiratory function is often aided through the use of mechanical ventilation or oxygen, which itself can induce injury. In the case of chronic disease or injury, immediate medical intervention does not always occur. The ability for the lung to compensate for loss of function due to injury or disease is tremendous [18, 19]; unfortunately, in the case of many degenerative diseases, once a patient has lost the majority of their lung function, and a diagnosis is finally made, treatment options become quite limited. Palliation of symptoms for patients who are less than ideal candidates for transplantation has become the standard course of treatment. Medications such as corticosteroids, oxygen therapy, and attempts at pulmonary rehabilitation are strategies often employed to further halt the progression of chronic disease. For patients who do receive lung transplants, pharmacologically based anti-rejection therapies must be employed for the remainder of the patient’s life.

The disparity of treatment options for lung injury and disease provides ample opportunity for the development of cellular therapies. Furthermore, the magnitude and diversity of injury and disease affecting the lung suggests that cellular therapies for the treatment of respiratory disease will most likely need to encompass a multitude of cell types and approaches to effectively treat specific diseases and specific stages within those diseases [20, 21]. In the lung, both endogenous and exogenous stem cell-based therapies have been investigated with varied success, as summarized in Table 6.3 [14].

Once a suitable stem cell-based treatment strategy has been devised, clinicians and scientists must determine appropriate delivery strategies. Cell-based therapies pose an interesting challenge in that, unlike pharmaceuticals, they are dynamic and can be responsive to the environments and conditions to which they are exposed [24–30]. Thus, careful consideration must be given to the desired outcome of the stem cell-based treatment, the clinical status of the patient, as well any secondary mechanisms that affect or are employed by the stem cell to ensure appropriate delivery to target locations (Table 6.4).

Thus, taking into account the aforementioned topics of development, anatomy and physiology and variety of diseases affecting the lung, one can begin to understand the complexity of designing any type of cellular therapy for the lung. The varied architecture and variety of cell types and litany of functions performed by these cells suggests that multiple cell types are perhaps required to treat the lung. For example, developmental and genetic abnormalities, such as in cystic fibrosis, resulting in deleterious respiratory phenotypes may require manipulation of stem cells, to overexpress and deliver functional CFTR protein, prior to treatment in order to compensate for endogenous abnormalities. In cases where injury or disease results in the minimal loss of organ function, such as in inhalation exposure, treatment strategies may focus on using stem cells to stimulate endogenous repair mechanisms to improve and promote wound healing. In cases of catastrophic loss of organ function (such as in acute respiratory distress syndrome, ARDS), or progressive disease (as in the case of pulmonary fibrosis), stem cell-based therapies may be useful to inhibit the progression of disease. Finally, in cases where total loss of organ function is inevitable, tissue and organ engineering using stem cells may be a logical treatment strategy. Interestingly, exogenous stem cells have been found within the amniotic fluid that has demonstrated varying levels of success within each of the aforementioned arenas.